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Advances in Therapy Jun 2023Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making...
INTRODUCTION
Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition.
METHODS
The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement.
RESULTS
Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence.
CONCLUSION
Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.
Topics: Humans; Hemoglobinuria, Paroxysmal; Expert Testimony; Complement Inactivating Agents; Complement C3; Complement C5; Europe
PubMed: 37072660
DOI: 10.1007/s12325-023-02510-4 -
The Thoracic and Cardiovascular Surgeon Jun 2024Extracorporeal membrane oxygenation (ECMO) has been increasingly applied over recent decades to treat severe cardiogenic shock and acute lung failure and cardiac arrest...
Extracorporeal membrane oxygenation (ECMO) has been increasingly applied over recent decades to treat severe cardiogenic shock and acute lung failure and cardiac arrest of various causes. Acute intoxication with therapeutic substances or other chemical substances can cause severe cardiogenic shock or even cardiac arrest. The purpose of this study was to conduct a qualitative systematic review of ECMO use in intoxication and poisoning. We searched the PubMed, Medline, and Web of Science databases from January 1971 to December 2021 and selected appropriate studies according to our inclusion and exclusion criteria to evaluate the role of ECMO in intoxication and poisoning systematically. Survival at hospital discharge was examined to describe the outcome. The search resulted in 365 publications after removing duplicates. In total, 190 full-text articles were assessed for eligibility. A total of 145 articles from 1985 to 2021 were examined in our final qualitative analysis. A total of 539 (100%) patients were included (mean age: 30.9 ± 16.6 years), with a distribution of = 64 (11.9%) cases with venovenous (vv) ECMO, = 218 (40.4%) cases with venoarterial (va) ECMO, and = 257 (47.7%) cases with cardiac arrest and extracorporeal cardiopulmonary resuscitation. Survival at hospital discharge was 61.0% for all patients, 68.8% for vaECMO, 75% for vvECMO, and 50.9% for extracorporeal cardiopulmonary resuscitation. When used and reported, ECMO seems to be a valid tool for adult and pediatric patients suffering intoxication from various pharmaceutical and nonpharmaceutical substances due to a high survival rate at hospital discharge.
Topics: Humans; Extracorporeal Membrane Oxygenation; Drug Overdose; Treatment Outcome; Risk Factors; Adult; Male; Female; Middle Aged; Young Adult; Adolescent; Child; Child, Preschool; Time Factors; Aged; Poisoning; Shock, Cardiogenic; Risk Assessment; Recovery of Function; Infant; Heart Arrest
PubMed: 36940708
DOI: 10.1055/s-0043-1764160 -
Knee Surgery, Sports Traumatology,... Aug 2023Aim of this systematic review was to determine if bone marrow-derived cell-based injectable therapies induce disease-modifying effects in joints affected by... (Review)
Review
Cell-based therapies have disease-modifying effects on osteoarthritis in animal models. A systematic review by the ESSKA Orthobiologic Initiative. Part 2: bone marrow-derived cell-based injectable therapies.
PURPOSE
Aim of this systematic review was to determine if bone marrow-derived cell-based injectable therapies induce disease-modifying effects in joints affected by osteoarthritis (OA) in animal models.
METHODS
A systematic review was performed on three electronic databases (PubMed, Web of Science, Embase) according to PRISMA guidelines. A synthesis of the results was performed investigating disease-modifying effects in preclinical animal studies comparing injectable bone marrow-derived products with OA controls or other products, different formulations or injection intervals, and the combination with other products. The risk of bias was assessed according to the SYRCLE's tool.
RESULTS
Fifty-three studies were included (1819 animals) with an increasing publication trend over time. Expanded cells were used in 48 studies, point-of-care products in 3 studies, and both approaches were investigated in 2 studies. Among the 47 studies presenting results on the disease-modifying effects, 40 studies (85%) reported better results with bone marrow-derived products compared to OA controls, with positive findings evident in 14 out of 20 studies (70%) in macroscopic assessment, in 30 out of 41 studies (73%) in histological assessment, and in 10 out of 13 studies (77%) in immunohistochemical evaluations. Clinical evaluations showed positive results in 7 studies out of 9 (78%), positive imaging results in 11 studies out of 17 (65%), and positive biomarker results in 5 studies out of 10 (50%). While 36 out of 46 studies (78%) reported positive results at the cartilage level, only 3 out of 10 studies (30%) could detect positive changes at the synovial level. The risk of bias was low in 42% of items, unclear in 50%, and high in 8%.
CONCLUSION
This systematic review of preclinical studies demonstrated that intra-articular injections of bone marrow-derived products can induce disease-modifying effects in the treatment of OA, slowing down the progression of cartilage damage with benefits at macroscopic, histological, and immunohistochemical levels. Positive results have been also observed in terms of clinical and imaging findings, as well as in the modulation of inflammatory and cartilage biomarkers, while poor effects have been described on the synovial membrane. These findings are important to understand the potential of bone marrow-derived products and to guide further research to optimise their use in the clinical practice.
LEVEL OF EVIDENCE
II.
Topics: Animals; Bone Marrow; Osteoarthritis; Synovial Membrane; Disease Models, Animal; Injections, Intra-Articular; Mesenchymal Stem Cell Transplantation; Osteoarthritis, Knee
PubMed: 36823238
DOI: 10.1007/s00167-023-07320-3 -
Frontiers in Immunology 2022Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT),... (Review)
Review
Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case-control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.
Topics: Adult; Child; Humans; Adolescent; Prognosis; Prospective Studies; Biomarkers; Graft vs Host Disease; Thrombotic Microangiopathies
PubMed: 36818475
DOI: 10.3389/fimmu.2022.1064203 -
Quintessence International (Berlin,... Mar 2023The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy of the use of systemic antibiotics in regenerative periodontal surgery for... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy of the use of systemic antibiotics in regenerative periodontal surgery for treating teeth affected by periodontitis.
DATA SOURCES
Electronic (MEDLINE, EMBASE, LILACS, Scopus, and Cochrane) and manual literature searches for human randomized controlled trial studies published up to November 2022 were conducted by two reviewers. Meta-analysis was performed to assess probing pocket depth (PPD) reduction and clinical attachment level (CAL) gain in groups receiving systemic antibiotics compared to those not receiving systemic antibiotics. A total of eight studies were included. While treated sites were intrabony defects in six papers, two studies focused on furcation defects. For intrabony defects, the weighted mean difference (WMD) of 0.30 mm (95% CI -0.18 to 0.78) and 0.27 mm (95% CI -0.13 to 0.66) was calculated for PPD reduction and CAL gain, respectively. The differences between antibiotics and non-antibiotics groups for PPD and CAL were not statistically significant. Quantitative analysis could not be performed for furcation defects due to the limited number of studies. However, regardless of the membrane type selection, the existing evidence indicated that antibiotics did not lead to superior clinical outcomes for furcation defects at 9 to 12 months after the regenerative procedures.
CONCLUSION
Based on this meta-analysis study's findings, the use of adjunct systemic antibiotics in regenerative periodontal surgery did not appear to achieve more favorable clinical outcomes. Thus, the use of adjunct systemic antibiotics as part of the regenerative periodontal therapy might not be justifiable and should be reconsidered. (Quintessence Int 2023;54:210-219; doi: 10.3290/j.qi.b3648957).
Topics: Humans; Furcation Defects; Randomized Controlled Trials as Topic; Periodontitis; Treatment Outcome; Regeneration; Guided Tissue Regeneration, Periodontal; Alveolar Bone Loss
PubMed: 36472512
DOI: 10.3290/j.qi.b3648957 -
Cancer Management and Research 2022Human papillomavirus targets the skin and mucous membranes, producing benign hyperplastic lesions and precancerous and cancerous lesions. An increasing number of head... (Review)
Review
BACKGROUND
Human papillomavirus targets the skin and mucous membranes, producing benign hyperplastic lesions and precancerous and cancerous lesions. An increasing number of head and neck cancersin particular, oropharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, and oral squamous cell carcinoma, are attributable to HPV infection. HPV-induced HNCs typically affect younger, nonsmoking patients with no prior history of heavy alcohol use, more extensive sexual history, and higher socioeconomic status.
AIM
The purpose of the review is to present the most recent and well-established findings concerning HPV-induced head and neck cancers and consequently to provide medical specialists with essential information regarding the epidemiology, the role of HPV in HNC cancerogenesis, prevention, diagnosis, and treatment.
MATERIAL AND METHODS
All authors independently have searched The EMbase, Medline/Pubmed, and Cochrane databases by using the following keywords "head and neck cancer", "human papillomavirus", "HPV", "HPV biology", "oropharyngeal squamous cell carcinoma", "carcinogenesis", "transoral surgery", "robotic surgery". The last search was conducted in March 2022. The references of the publications of interest were also screened for relevant papers. There were no limitations in regard to the publication date.
CONCLUSION
Aiming to avoid the epidemic of HPV-induced HNC, it is paramount to improve the access to vaccination as well as resolve parental concerns regarding vaccine safety. Physicians should rely on reduced-dose radiation and aim to reduce the overall treatment time. Thanks to a more elaborate understanding of the genomic background of HPV-induced HNC, precision medicine could become a relevant part of patients' management. In comparison to traditional techniques and non-operative treatment, transoral robotic surgery (TORS) offers similar oncologic and functional outcomes, with a possible benefit on long-term quality of life. However, more research is needed to establish clear guidelines indicating when TORS resections should be supported with adjuvant therapy.
PubMed: 36465708
DOI: 10.2147/CMAR.S379173 -
Orthopaedic Surgery Jan 2023Several modifications of the induced membrane technique (IMT) have been reported, but there is no consensus regarding their results and prognosis. Moreover, most studies... (Meta-Analysis)
Meta-Analysis Review
Several modifications of the induced membrane technique (IMT) have been reported, but there is no consensus regarding their results and prognosis. Moreover, most studies have focused on tibial defects; no meta-analysis of the treatment of femoral defects using the IMT has been reported. This systematic review and meta-analysis aimed to identify the potential risk factors of post-procedural complications following the treatment of segmental femoral defects using the IMT. A comprehensive search was performed on the Cochrane Library, EBSCO, EMBASE, Ovid, PubMed, Scopus, and Web of Science databases, using the keywords "femur," "Masquelet technique," and "induced membrane technique." Original articles composed in English, having accessible individual patient data, and reporting more than two cases of bony defect or nonunion of femur or more than five cases of any body part were included. Post-procedural bone graft infections, final union status, and union time after second-stage operation were analyzed. Fourteen reports, including 90 patients, were used in this study. External fixation in second-stage surgery had an odds ratio of 9.267 for post-procedural bone graft infection (p = 0.047). The odds ratio of post-procedural bone graft infection and age >65 years for final non-union status was 51.05 (p = 0.003) and 9.18 (p = 0.042). Shorter union time was related to impregnated antibiotics in the spacer (p = 0.005), transplanting all-autologous grafts (p = 0.042), and the application of intramedullary nails as the second-stage fixation method (p = 0.050). The IMT appears to be reasonable and reproducible for femoral segmental bone defects. Several preoperative and surgical factors may affect post-procedural complications and union time.
Topics: Humans; Aged; Femur; Tibia; Prognosis; Fracture Fixation, Intramedullary; Anti-Bacterial Agents; Bone Transplantation; Treatment Outcome
PubMed: 36444955
DOI: 10.1111/os.13604 -
Frontiers in Oncology 2022Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The...
Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The endoplasmic reticulum (ER) is the organelle where proteins undergo post-translational modifications and are folded and exported to the secretory pathway. Its environment and activity are therefore fundamental for proteostasis, i.e., the plethora of mechanisms controlling protein formation, folding, degradation, and secretion, needed to assure protein balance and cellular health. In different tumor-related conditions, such as after the activation of oncogenes or under hypoxia and nutrient deprivation, the ER experiences stress, triggered by a high load of proteins to be folded compared to the limited folding capacity of the organelle. As a consequence, three ER membrane sensors and the related unfolded protein response (UPR) are activated. The UPR comprises a complex interconnection between signal transduction pathways that promote a homeostatic response that acts by increasing the amount of protein chaperones and of proteins involved in ER-associated protein degradation (ERAD) on one hand and attenuating protein translation on the other. ER-phagy, literally "eating" the ER, is part of another homeostatic response consisting of the clearance of non-functional ER portions including misfolded proteins. This response is also activated by a set of dedicated ER-phagy receptors after ER stimuli, which overlap the stimuli generating ER stress. Thus, the UPR and ER-phagy are two closely related homeostatic mechanisms that cooperate in re-establishing ER homeostasis. However, while the role of the UPR in favoring cancer growth and thriving by promoting angiogenesis, metastasis, chemotherapy resistance, and epithelial-to-mesenchymal transition is consolidated, that of ER-phagy is still in its infancy. This essay provides an overview of emerging concepts on ER stress, the UPR, and ER-phagy and their crosstalk in tumorigenesis. We also critically review new findings on their pharmacological targeting in cancer.
PubMed: 36408145
DOI: 10.3389/fonc.2022.997235 -
ASAIO Journal (American Society For... Jan 2023Right ventricular injury (RVI) in the context of acute respiratory distress syndrome (ARDS) is well recognized as an important determinant risk factor of mortality.... (Meta-Analysis)
Meta-Analysis
Right Ventricular Injury Increases Mortality in Patients With Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.
Right ventricular injury (RVI) in the context of acute respiratory distress syndrome (ARDS) is well recognized as an important determinant risk factor of mortality. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is part of the algorithm for the management of patients with severe ARDS and severely impaired gas exchange. Although VV-ECMO may theoretically protect the RV it is uncertain to what degree RVI persists despite VV-ECMO support, and whether it continues to influence mortality after ECMO initiation. The aim of this systematic review and meta-analysis was to investigate the impact of RVI on mortality in this context, testing the hypothesis that RVI worsens mortality in this cohort. We performed a systematic search that identified seven studies commenting on RVI and mortality in patients with ARDS receiving VV-ECMO. The presence of RVI was associated with greater mortality overall (odds ratios [OR]: 2.72; 95% confidence intervals [CI]: 1.52-4.85; p < 0.00) and across three subgroups (RV dilatational measures: OR: 3.51; 95% CI: 1.51-8.14; p < 0.01, RV functional measures: OR: 1.84; 95% CI: 0.99-3.42; p = 0.05, RV measurements post-ECMO initiation: OR: 1.94; 95% CI: 1.01-3.72; p < 0.05). Prospective studies are needed to investigate the causal relationship between RVI and mortality in this patient group and the best management strategies to reduce mortality.
Topics: Humans; Extracorporeal Membrane Oxygenation; Respiratory Distress Syndrome; Risk Factors; Heart Ventricles; Retrospective Studies
PubMed: 36375040
DOI: 10.1097/MAT.0000000000001854 -
Frontiers in Immunology 2022The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is...
BACKGROUND
The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging.
OBJECTIVE
We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components.
METHODS
A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses.
RESULTS
A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used.
CONCLUSION
A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis.
Topics: Humans; Complement C5; Complement Activation; Complement C3; Complement Membrane Attack Complex; Biomarkers
PubMed: 36330514
DOI: 10.3389/fimmu.2022.1007102