bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature
Authors: Liu Lisa L , Skribek Marcus , Harmenberg Ulrika , Gerling Marco 
Published: March 2023

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions.Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation.We further provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase and the Web of Science Core Collection from inception to October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n=1866 articles, which were assessed for eligibility independently by two examiners. Of those, n=49 articles reporting on n=189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment were reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial under-reporting.The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.
Implication of99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells
Authors: Gao Yu , Luo Qi , Sun Zhichen , Gao Hannan , Yu Yue , Sun Yining , Ma Xiaotu , Han Chuanhui , Shi Jiyun , Wang Fan 
Published: March 2023

BackgroundAlthough immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe99mTc-sum IL-2 targeting the IL-2Rβ/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy.MethodsThe binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with99mTc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of99mTc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated99mTc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy.ResultsSum IL-2 preferentially bound to CD8+T cells, especially activated CD8+T cells, while IL-2 showed biased binding to Treg cells. As a result,99mTc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of99mTc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition,99mTc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8+T cells during ACT therapy.Conclusion99mTc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy.
Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma
Authors: Frias Alex , Di Leo Luca , Antoranz Asier , Nazerai Loulieta , Carretta Marco , Bodemeyer Valérie , Pagliuca Chiara , Dahl Christina , Claps Giuseppina , Mandelli Giulio Eugenio , Andhari Madhavi Dipak , Pacheco Maria Pires , Sauter Thomas , Robert Caroline , Guldberg Per , Madsen Daniel Hargbøl , Cecconi Francesco , Bosisio Francesca Maria , De Zio Daniela 
Published: March 2023

BackgroundLoss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.MethodsThis study was performed using an Ambra1-depletedBrafV600E/Pten−/−genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts ofBrafV600E/Pten−/−andBrafV600E/Pten−/−/Cdkn2a−/−tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis inBrafV600E/Pten−/−/Cdkn2a−/−mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor.ResultsLoss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In theBrafV600E/Pten−/−/Cdkn2a−/−model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment.ConclusionsThis study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.
CT-guided percutaneous cyanoacrylate injection targeting the spinal cerebrospinal fluid leak: a potential therapeutic option for spontaneous intracranial hypotension
Authors: Liao Liang , Tonnelet Romain , Schmitt Emmanuelle , Planel Sophie , Zhu François , Muszynski Patricio , Harsan Oana , Anxionnat René , Bracard Serge , Braun Marc 
Published: March 2023

Background
We report the first case series of spontaneous intracranial hypotension (SIH) patients who underwent CT-guided percutaneous cyanoacrylate injection targeting the cerebrospinal fluid (CSF) leak.

Methods

A retrospective analysis was performed for all consecutive cases of SIH patients with CSF leak confirmed on CT myelography, treated by CT-guided percutaneous cyanoacrylate injection at our institution from 2016 to 2022. On pretreatment brain and spine MRIs, we analyzed signs of SIH according to the Bern score, and dichotomized cases into positive/negative for spinal longitudinal extradural CSF collection (SLEC-P or SLEC-N). The leaks detected on CT myelography were classified into three types according to Schievink
et al
. We collected the Headache Impact Test 6 (HIT-6) scores throughout a 6-month follow-up, with a brain CT scan at each visit.

Results
11 patients were included (mean age 48.4 years, six men). Five SLEC-P type 1, three SLEC-P type 2, and three SLEC-N type 3 leaks were identified. All patients had significant signs of SIH on pretreatment brain MRI (mean Bern score 7.8±1.1). Six patients underwent a foraminal puncture, and five patients had a cervical epidural approach. Two patients experienced mild and transient locoregional pain after cervical epidural injection. Mean HIT-6 score at baseline was 66.8±3.2 and at the 6-month follow-up was 38±3.6 (P<0.001). All patients achieved improvement in their symptoms, with 82% of them (9/11) having complete resolution of headaches and SIH findings on CT scans at 6 months. No clinical worsening or recurrence was observed.

Conclusions
CT-guided percutaneous cyanoacrylate injection may be a potential therapeutic option for the different types of CSF leak causing SIH.
Generic and disease-adapted cardiovascular risk scores as predictors of atherosclerosis progression in SLE
Authors: Panopoulos Stylianos , Drosos George C , Konstantonis George , Sfikakis Petros P , Tektonidou Maria G 
Published: March 2023

ObjectiveStudies show that generic cardiovascular risk (CVR) prediction tools may underestimate CVR in SLE. We examined, for the first time to our knowledge, whether generic and disease-adapted CVR scores may predict subclinical atherosclerosis progression in SLE.MethodsWe included all eligible patients with SLE without a history of cardiovascular events or diabetes mellitus, who had a 3-year carotid and femoral ultrasound follow-up examination. Five generic (Systematic Coronary Risk Evaluation (SCORE), Framingham Risk Score (FRS), Pooled Cohort Risk Equation, Globorisk, Prospective Cardiovascular Münster) and three ‘SLE-adapted’ CVR scores (modified Systematic Coronary Risk Evaluation (mSCORE), modified Framingham Risk Score (mFRS), QRESEARCH Risk Estimator V.3 (QRISK3)) were calculated at baseline. The performance of CVR scores to predict atherosclerosis progression (defined as new atherosclerotic plaque development) was tested with Brier Score (BS), area under the receiver operating characteristic curve (AUROC) and Matthews correlation coefficient (MCC), while rank correlation was tested with Harrell’sc-index. Binary logistic regression was also applied to examine determinants of subclinical atherosclerosis progression.ResultsTwenty-six (21%) of 124 included patients (90% female, mean age 44.4±11.7 years) developed new atherosclerotic plaques after a mean of 39.7±3.8 months’ follow-up period. Performance analysis showed that plaque progression was better predicted by the mFRS (BS 0.14, AUROC 0.80, MCC 0.22) and QRISK3 (BS 0.16, AUROC 0.75, MCC 0.25).c-Index showed no superiority for discrimination between mFRS and QRISK3. In the multivariate analysis, QRISK3 (OR 4.24, 95% CI 1.30 to 13.78, p=0.016) among the CVR prediction scores and age (OR 1.13, 95% CI 1.06 to 1.21, p<0.001), cumulative glucocorticoid dose (OR 1.04, 95% CI 1.01 to 1.07, p=0.010) and antiphospholipid antibodies (OR 3.66, 95% CI 1.24 to 10.80, p=0.019) among disease-related CVR factors were independently associated with plaque progression.ConclusionsApplication of SLE-adapted CVR scores such as QRISK3 or mFRS, as well as monitoring for glucocorticoid exposure and the presence of antiphospholipid antibodies, can help to improve CVR assessment and management in SLE.
Diagnostic performance of a device for acoustic heart sound analysis in patients with suspected myocardial infarction
Authors: Lehmacher Jonas , Neumann Johannes T , Sörensen Nils Arne , Goßling Alina , Schmidt Samuel Emil , Zeller Tanja , Blankenberg Stefan , Westermann Dirk , Clemmensen Peter M 
Published: March 2023

BackgroundAs only a small proportion of patients with chest pain suffers from myocardial infarction (MI), safe rule-out of MI is of immense importance. Recently an ultrasensitive microphone performing diastolic heart sound analysis (CADScorSystem) for rule-out of coronary artery disease (CAD) has emerged. In this explorational study, we aimed to evaluate the feasibility of the CADScorSystem for diagnosis of MI in the setting of a large emergency department.MethodsPatients presenting to the emergency department with suspected MI were included. Acoustic heart sound analysis was performed in all patients and automated CAD-score values were calculated via a device-embedded algorithm, which also requires inclusion of three clinical variables: age, sex and presence of hypertension. Patients additionally received serial high-sensitive troponin T measurement measurements to assess the final diagnosis according to third Universal Definition of Myocardial Infarction applying the European Society of Cardiology 0 hour/3 hours algorithm. Diagnostic parameters for MI, considering different CAD-score cut-offs, were computed.ResultsOf 167 patients, CAD-scores were available in 61.1%. A total of eight patients were diagnosed with MI. At a cut-off value of <20, CAD-score had a negative predictive value (NPV) of 90.7 (78.4–96.3). The corresponding positive predictive value (PPV) was 6.8 (2.7–16.2). For the adjusted CAD-score (age, sex, hypertension), at a cut-off value of <20, NPV was 90.0 (59.6–99.5) with a PPV of 10.8 (5.3–20.6).ConclusionIn this explorative analysis, a transcutaneous ultrasensitive microphone for heart sound analysis resulted in a high NPV analogous to the findings in rule-out of stable CAD in elective patients yet inferior to serial high-sensitivity cardiac troponin measurements and does not seem feasible for application in an emergency setting for rule-out of MI.Trial registration numberNCT02355457.
Harnessing digital health to optimise the delivery of guideline-based cardiac rehabilitation during COVID-19: an observational study
Authors: Gibson Irene , McCrudden Zoe , Dunne Denise , Harris Aisling , Hynes Lisa , Murphy Ella , Murphy Andrew William , Byrne Molly , McEvoy John William 
Published: March 2023

BackgroundThe COVID-19 pandemic accelerated the uptake of digital health interventions for the delivery of cardiac rehabilitation (CR). However, there is a need to evaluate these interventions.MethodsWe examined the impact of an evidence-based, digital CR programme on medical, lifestyle and psychosocial outcomes. Delivered by an interdisciplinary team of healthcare professionals, the core components of this 12-week programme included lifestyle modification, medical risk factor management, psychosocial and behavioural change support. To support self-management, patients were provided with a Fitbit, a home blood pressure (BP) monitor and an interactive workbook. Patients received access to a bespoke web-based platform and were invited to attend weekly, online group-based supervised exercise sessions and educational workshops. Outcomes were assessed at baseline, end of programme and at 6-month follow-up.ResultsOver a 3-month period, 105 patients (88% with coronary heart disease) were referred with 74% (n=77) attending initial assessment. Of these, 97% (n=75) enrolled in the programme, with 85% (n=64) completing the programme, 86% (n=55) of completers attended 6-month follow-up. Comparing baseline to end of programme, we observed significant improvements in the proportion of patients meeting guideline-recommended targets for physical activity (+68%, p<0.001), BP (+44%, p<0.001) and low-density lipoprotein cholesterol (+27%, p<0.001). There were significant reductions in mean weight (−2.6 kg, p<0.001). Adherence to the Mediterranean diet score improved from 5.2 to 7.3 (p<0.001). Anxiety and depression levels (Hospital Anxiety and Depression score) both reduced by more than 50% (p<0.001). The majority of these improvements were sustained at 6-month follow-up.ConclusionOutcomes from this study suggest that interdisciplinary digital CR programmes can be successfully implemented and help patients achieve guideline recommended lifestyle, medical and therapeutic targets.
Caesarean section in women with axial spondyloarthritis and psoriatic arthritis: a population-based study
Authors: Götestam Skorpen Carina , Lydersen Stian , Salvesen Kjell Åsmund , Koksvik Hege Suorza Svean , Jakobsen Bente , Wallenius Marianne 
Published: March 2023

BackgroundThere is sparse documentation on pregnancy outcomes in women with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). Data on disease activity are often lacking, preventing the direct investigation of the effect of inflammation on pregnancy outcomes. A caesarean section (CS) implies a higher risk for complications than vaginal delivery. It delays mobilisation after birth necessary to counteract inflammatory pain and stiffness.ObjectiveTo explore a possible association of inflammatory active disease and CS rates in women with axSpA and PsA.MethodsData from the Medical Birth Registry of Norway (MBRN) were linked with data from RevNatus, a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases. Singleton births in women with axSpA (n=312) and PsA (n=121) included in RevNatus 2010–2019 were cases. Singleton births, excluding mothers with rheumatic inflammatory diseases, registered in MBRN during the same period time (n=575 798) served as population controls.ResultsCS occurred more frequently in both axSpA (22.4%) and PsA (30.6%) groups compared with population controls (15.6%), with even higher frequencies in inflammatory active axSpA (23.7%) and PsA (33.3%) groups. Compared with population controls, women with axSpA had higher risk for elective CS (risk difference 4.4%, 95% CI 1.5% to 8.2%) but not emergency CS. Women with PsA had higher risk for emergency CS (risk difference 10.6%, 95% CI 4.4% to 18.7%) but not elective CS.ConclusionWomen with axSpA had higher risk for elective and women with PsA for emergency CS. Active disease amplified this risk.
Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease: an extension study (RESCUE 2)
Authors: Tran Ai Phuong , Tassone D.F , Ding N S , Nossent Johannes 
Published: March 2023

The persistence of immunogenicity in patients with immune-mediated inflammatory diseases (IMID) on disease-modifying antirheumatic therapy (DMARD) has been less well studied. This extension study evaluates the SARS-CoV2 antibody decay kinetics 6 months following two doses of ChAdO1nCov-19 (AZ) and BNT162b (Pfizer) and subsequent response following an mRNA booster.Results175 participants were included. Six months after initial AZ vaccination, 87.5%, 85.4% and 79.2% (p=0.756) in the withhold, continue and control groups remained seropositive compared with 91.4%, 100% and 100% (p=0.226), respectively, in the Pfizer group. Both vaccine groups developed robust humoral immune responses following a booster with seroconversion rates being 100% for all three intervention categories. The mean SARS-CoV-2 antibody levels were significantly lower in the targeted synthetic DMARD (tsDMARD) group that continued therapy compared with the control (2.2 vs 4.8 U/mL, p=0.010). The mean time interval until loss of protective antibodies in the IMID group was 61 days for the AZ and 137.5 days for the Pfizer vaccine. Within each DMARD class the interval until loss of protective antibody titres in the csDMARD, bDMARD and tsDMARD groups were 68.3, 71.8 and 64.0 days in the AZ group and 185.5, 137.5 and 116.0 days in the Pfizer group, respectively.ConclusionAntibody persistence was longer in the Pfizer group due to a higher peak antibody level following second vaccination with levels of protection in IMID on DMARD therapy similar to controls except in those on tsDMARDs where it was lower. A third mRNA vaccine booster can restore immunity in all groups.
Points to consider for cost-effective use of biological and targeted synthetic DMARDs in inflammatory rheumatic diseases: results from an umbrella review and international Delphi study
Authors: van der Togt Céleste J T , Van den Bemt Bart , Aletaha Daniel , Alten Rieke , Chatzidionysiou Katerina , Galloway James , Isaac John , Mulleman Denis , Verschueren P , Vulto Arnold G , Welsing Paco M J , Verhoef Lise , den Broeder Alfons A 
Published: March 2023

ObjectivesTo develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis.MethodsFollowing EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a–5) and grade (A–D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously.ResultsThe task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity–guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4).ConclusionThese points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment.