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All forms of cerebral inflammation as found in bacterial meningitis, cerebral malaria, brain injury, and subarachnoid haemorrhage have been associated with vasospasm of cerebral arteries and arterioles. Vasospasm has been associated with permanent neurological deficits and death in subarachnoid haemorrhage and bacterial meningitis. Increased levels of interleukin-1 may be involved in vasospasm through calcium dependent and independent activation of the myosin light chain kinase and release of the vasoconstrictor endothelin-1. Another key factor in the pathogenesis of cerebral arterial vasospasm may be the reduced bioavailability of the vasodilator nitric oxide. Therapeutic trials in vasospasm related to inflammation in subarachnoid haemorrhage in humans showed a reduction of vasospasm through calcium antagonists, endothelin receptor antagonists, statins, and plasminogen activators. Combination of therapeutic modalities addressing calcium dependent and independent vasospasm, the underlying inflammation, and depletion of nitric oxide simultaneously merit further study in all conditions with cerebral inflammation in double blind randomised placebo controlled trials. Auxiliary treatment with these agents may be able to reduce ischemic brain injury associated with neurological deficits and increased mortality.

In children with meningococcal septicemia-associated pulmonary edema ventilated on a pediatric intensive care unit, we detected increased sweat and salivary chloride and sodium levels in patients with septicemia-related pulmonary edema. Exhaled breath condensate (EBC) gained from the outgoing tubing of ventilators in patients ventilated because of respiratory failure from sepsis-related pulmonary edema or pneumonia could be gained following standardized and internationally recognized methods (4,5) and analyzed for chloride and sodium levels relating these levels to urea concentrations to correct for evaporation and dilution and correcting for salivary contamination by amylase measurement. Conflict of Interest Statement The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1WeidenfeldSKueblerWM.Cytokine-regulation of Na+-K+-Cl- cotransporter 1 and cystic fibrosis transmembrane conductance regulator-potential role in pulmonary inflammation and edema formation.Front Immunol(2017)8:393.10.3389/fimmu.2017.00393 2EisenhutMWallaceHBartonPGaillardENewlandPDiverMPulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.Pediatr Crit Care Med(2006)7(2):119–24.10.1097/00130478-200603000-00032 3NakamuraHYoshimuraKBajocchiGTrapnellBCPaviraniACrystalRG.Tumor necrosis factor modulation of expression of the cystic fibrosis transmembrane conductance regulator gene.FEBS Lett(1992)314(3):366–70.10.1016/0014-5793(92)81507-I 4CarterSRDavisCSKovacsEJ.Exhaled breath condensate collection in the mechanically ventilated patient.Respir Med(2012)106(5):601–13.10.1016/j.rmed.2012.02.00322398157 5HorváthIHuntJBarnesPJAlvingKAntczakABaraldiEExhaled breath condensate: methodological recommendations and unresolved questions.Eur Respir J(2005)26:523–48.10.1183/09031936.05.0002970516135737 6ZacharasiewiczAWilsonNLexCLiAKempMDonovanJRepeatability of sodium and chloride in exhaled breath condensates.Pediatr Pulmonol(2004)37:273–5.10.1002/ppul.1043114966822

Purpose The clinical introduction of 68 Ga-PSMA-11 (“HBED-CC”) ligand targeting the prostate-specific membrane antigen (PSMA) has been regarded as a significant step forward in the diagnosis of prostate cancer (PCa). In this study, we provide human dosimetry and data on optimal timing of PET imaging after injection. Methods Four patients with recurrent PCa were referred for 68 Ga-PSMA-11 PET/CT. Whole-body PET/CT low-dose scans were conducted at 5 min, and 1, 2, 3, 4 and 5 h after injection of 152–198 MBq 68 Ga-PSMA-11. Organs of moderate to high uptake were used as source organs; their total activity was determined at all measured time points. Time–activity curves were created for each source organ as well as for the remainder. The radiation exposure of a 68 Ga-PSMA-11 PET was identified using the OLINDA-EXM software. In addition, tracer uptake was measured in 16 sites of metastases. Results The highest tracer uptake was observed in the kidneys, liver, upper large intestine, and the urinary bladder. Mean organ doses were: kidneys 0.262 ± 0.098 mGy/MBq, liver 0.031 ± 0.004 mGy/MBq, upper large intestine 0.054 ± 0.041 mGy/MBq, urinary bladder 0.13 ± 0.059 mGy/MBq. The calculated mean effective dose was 0.023 ± 0.004 mSv/MBq (=0.085 ± 0.015 rem/mCi). Most tumor lesions ( n  = 16) were visible at 3 h p.i., while at all other time points many were not qualitatively present (10/16 visible at 1 h p.i.). Conclusions The mean effective dose of a 68 Ga-PSMA-11 PET is 0.023 mSv/MBq. A 3-h delay after injection was optimal timing for 68 Ga-PSMA-11 PET/CT in this patient cohort.

The diaphragm is the primary muscle of respiration. Here, we disclose a fascinating patient’s perspective that led, by clinical reasoning alone, to a novel mechanism of spontaneous respiratory arrests termed diaphragm cramp-contracture (DCC). Although the 7-year-old boy survived its paroxysmal nocturnal “bearhug pain apnea” episodes, essentially by breathing out to breathe in, DCC could cause sudden unexpected deaths in children, especially infants. Diaphragm fatigue is central to the DCC hypothesis in SIDS. Most, if not all, SIDS risk factors contribute to it, such as male sex, young infancy, rebreathing, nicotine, overheating and viral infections. A workload surge by a roll to prone position or REM-sleep inactivation of airway dilator or respiratory accessory muscles can trigger pathological diaphragm excitation (e.g., spasms, flutter, cramp). Electromyography studies in preterm infants already show that diaphragm fatigue and sudden temporary failure by transient spasms induce apneas, hypopneas and forced expirations, all leading to hypoxemic episodes. By extension, prolonged spasm as a diaphragm cramp would induce sustained apnea with severe hypoxemia and cardiac arrest if not quickly aborted. This would cause a sudden, rapid, silent death consistent with SIDS. Moreover, a unique airway obstruction could develop where the hypercontracted diaphragm resists terminal inspiratory efforts by the accessory muscles. It would disappear postmortem. SIDS autopsy evidence consistent with DCC includes disrupted myofibers and contraction band necrosis as well as signs of agonal breathing from obstruction. Screening for diaphragm injury from hypoxemia, hyperthermia, viral myositis and excitation include serum CK-MM and skeletal troponin-I. Active excitation could be visualized on ultrasound or fluoroscopy and monitored by respiratory inductive plethysmography or electromyography.

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.

The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clinical impact during the last years. 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this molecule represents a rather rarely used acyclic complexing agent with chemical characteristics favourably influencing the biological functionality of the PSMA inhibitor. The simple replacement of HBED-CC by the prominent radiometal chelator DOTA was shown to dramatically reduce the in vivo imaging quality of the respective 68Ga-labelled PSMA-targeted tracer proving that HBED-CC contributes intrinsically to the PSMA binding of the Glu-urea-Lys(Ahx) pharmacophore. Owing to the obvious growing clinical impact, this work aims to reflect the properties of HBED-CC as acyclic radiometal chelator and presents novel preclinical data and relevant aspects of the radiopharmaceutical production process of [68Ga]Ga-PSMA-HBED-CC.

Purpose Allergic and non-allergic rhinorrhea in the forms of acute or chronic rhinosinusitis can mean a watery nasal discharge that is disabling. Primary objective was to review the evidence supporting the hypothesis that rhinorrhea is due to increased chloride secretion through the CFTR chloride channel. Methods The structure of the evidence review followed the EQUATOR Reporting Guidelines. Databases searched from inception to February 2022 included Pubmed, EMBASE and the Cochrane library using keywords “Rhinorrhea”, “chloride”, “chloride channel”, “CFTR” and “randomized controlled trial”. Quality assessment was according to the Oxford Centre for Evidence-based Medicine. Results 49 articles were included. They included randomized controlled trials out of which subsets of data with the outcome of rhinorrhea on 6038 participants were analysed and in vitro and animal studies. The review revealed that drugs, which activate CFTR are associated with rhinorrhea. Viruses, which cause rhinorrhea like rhinovirus were found to activate CFTR. The chloride concentration in nasal fluid showed an increase in patients with viral upper respiratory tract infection. Increased hydrostatic tissue pressure, which is an activator of CFTR was observed in allergic upper airway inflammation. In this condition exhaled breath condensate chlorine concentration was found to be significantly increased. Drugs, which can reduce CFTR function including steroids, anti-histamines, sympathomimetic and anticholinergic drugs reduced rhinorrhea in randomized controlled trials. Conclusions A model of CFTR activation-mediated rhinorrhea explains the effectiveness of anticholinergic, sympathomimetic, anti-histamine and steroid drugs in reducing rhinorrhea and opens up avenues for further improvement of treatment by already known specific CFTR inhibitors.

Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.

Multiple myeloma (MM), a cancer of the bone marrow, is categorized as the second most common hematological malignancy of adults in the Western world. Despite dramatic improvements in immunotherapies in the field of cancers, MM immunotherapy has not been promising until now. Recent clinical studies of immune checkpoint inhibitor therapy, either alone or in combination with anticancer drugs, showed excessive side effects or low efficacy, particularly in advanced MM patients. In this context, lymphocyte levels of exhaustion markers play a pivotal role in the MM tumor microenvironment (TME). Hence in the present review, the mechanisms relevant to MM of five inhibitory molecules including T-cell immunoreceptor with Ig and ITIM domains (TIGIT), T-cell immunoglobulin, and mucin domain 3 (Tim-3), lymphocyte activation gene-3 (LAG-3), V-domain Ig Suppressor of T-cell activation and killer immunoglobulin-like receptors along with bispecific T-cell antibodies (BsAbs) will be discussed. Further, we summarized the underlying biology of these checkpoints in cancer and their rapidly emerging role in pathways in MM along with presenting recent clinical trials in context.

Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians.