The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) without driver ...alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately.
The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019.
This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed.
Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score TPS ≥ 50%) and non-squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non-platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines.
To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer without ...driver alterations.
ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021.
This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety.
In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score TPS ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive PD-L1 expression, SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models ...have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS.
Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS.
An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review.
Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials.
IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain. Significant research efforts have resulted in a paradigm shift away from identifying noninfectious lung injury after HSCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process involving aspects of both the adaptive and the innate immune response. Importantly, new laboratory insights are currently being translated to the clinic and will likely prove important to the development of future strategies to prevent or treat this serious disorder.
The aim of this study was to determine whether arthrocentesis is superior to conservative treatment in the management of painful temporomandibular joint disorders with restricted opening. A ...systematic review was undertaken of prospective randomized controlled trials (RCT) comparing arthrocentesis to conservative management, identified in the MEDLINE and PubMed databases. Inclusion criteria included a 6-month follow-up, with clinical assessment of the patients and painful restricted mouth opening. Data extracted included pain measured on a visual analogue scale and maximum mouth opening measured in millimetres. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2 for RCTs, and a meta-analysis with the random-effects model was undertaken. Of 879 records retrieved, seven met the inclusion criteria; these RCTs reported the results at 6 months for 448 patients. One study had a low risk of bias, four studies had an uncertain risk, and two had a high risk of bias. In the meta-analysis, arthrocentesis was statistically superior to conservative management at 6 months for an increase in maximum mouth opening (1.12 mm, 95% confidence interval 0.45–1.78 mm; P = 0.001; I2 = 87%) and borderline superior for pain reduction (−1.09 cm, 95% confidence interval −2.19 to 0.01 cm; P = 0.05; I2 = 100%). However, these differences are unlikely to be clinically relevant.
Objective
Following Porphyromonas gingivalis infection in mice, the efficacy of vaccination by recombinant and native RgpA in modulating the early local anti‐inflammatory and immune responses and ...periodontal bone loss were examined.
Material and Methods
Using the subcutaneous chamber model, exudates were analyzed for cytokines after treatment with native RgpA and adjuvant (test), or adjuvant and saline alone (controls). Mice were also immunized with recombinant RgpA after being orally infected with P. gingivalis. After 6 wk, serum was examined for anti‐P. gingivalis IgG1 and IgG2a titers and for alveolar bone resorption.
Results
Immunization with native RgpA shifted the immune response toward an anti‐inflammatory response as demonstrated by decreased proinflammatory cytokine IL‐1β production and greater anti‐inflammatory cytokine IL‐4 in chamber exudates. Systemically, immunization with recombinant RgpA peptide prevented alveolar bone loss by 50%, similar to immunization with heat‐killed whole bacteria. Furthermore, recombinant RgpA shifted the humoral response toward high IgG1 and low IgG2a titers, representing an in vivo anti‐inflammatory response.
Conclusions
The present study demonstrates the potential of RgpA to shift the early local immune response toward an anti‐inflammatory response while vaccination with recRgpA protected against P. gingivalis‐induced periodontitis.
Silybum marianum (milk thistle) is a Mediterranean plant that has been used since Greco-Roman times to treat liver ailments. Silibinin, the most active hepatoprotective constituent of the plant's ...seed, possesses antioxidant and anti-inflammatory properties. We thus assessed its protective potential in liver transplantation injury.
Rat livers were isolated and preserved during 24
h at 4
°C in University of Wisconsin (UW) solution alone (control), UW containing 100
μM silibinin or UW containing vehicle (ethanol). Livers were then reperfused at 37
°C for 1
h with Krebs–Henseleit solution supplemented with 20% erythrocytes.
Compared to control, cold preservation and warm reperfusion promoted lipid peroxidation (+40%) and superoxide anion generation (+147%), while attenuating reduced glutathione (−23%), mitochondrial ATP content (−57%) and respiratory control ratio (RCR; −37%). Preservation done in presence of silibinin improved parameters affected by preservation and reperfusion. In fact, silibinin promoted an increase of ATP and RCR by, respectively, 39 and 16% and decreased oxidative stress to values observed in livers never preserved nor perfused.
In conclusion, silibinin shows promise in protecting the liver from cold preservation/warm reperfusion damages. Moreover our study suggests that concepts of traditional medicine have the potential to be transposed successfully in the context of modern medical interventions such as liver transplantation surgery.
The aim of this study was to investigate the involvement of autoimmune reactions to native and post-translationally modified extracellular matrix components in the pathogenesis of periodontitis. Sera ...from individuals with aggressive periodontitis (AgP, n = 25), chronic periodontitis (CP, n = 14), and gingivitis (G, n = 18) were tested for the presence of autoantibodies against: (a) native collagen type I (CI) and collagen type III (CIII); (b) CI and CIII post-translationally modified by reactive oxygen species (ROS) of the type present during inflammation; and (c) citrullinated filaggrin-derived peptides (CCP). Autoantibodies to native and ROS-modified CI and CIII as well as autoantibodies to CCP were observed exclusively in patients with AgP and not in those with CP or G. In conclusion, autoimmune reactions to native and post-translationally modified self-antigens may play a role specifically in the pathogenesis of AgP.
Aim:Nigella sativa (N. sativa) is a plant widely used in traditional medicine of North African countries. During the last decade, several studies have shown that extracts from the seeds of N. sativa ...have antidiabetic effects. Methods: Our group has recently demonstrated that N. sativa seed ethanol extract (NSE) induces an important insulin-like stimulation of glucose uptake in C2C12 skeletal muscle cells and 3T3-L1 adipocytes following an 18 h treatment. The purpose of the present study was to elucidate the pathways mediating this insulin-like effect and the mechanisms through which these pathways are activated. Results: Results from western immunoblot experiments indicate that in C2C12 cells as well as in H4IIE hepatocytes, but not in 3T3-L1 cells, NSE increases activity of Akt, a key mediator of the effects of insulin, and activity of AMP-activated protein kinase (AMPK), a master metabolic regulating enzyme. To test whether the activation of AMPK resulted from a disruption of mitochondrial function, the effects of NSE on oxygen consumption were assessed in isolated liver mitochondria. NSE was found to exhibit potent uncoupling activity. Conclusion: Finally, to provide an explanation for the effects of NSE in adipocytes, PPARγ stimulating activity was tested using a reporter gene assay. Results indicate that NSE behaves as an agonist of PPARγ. The data supports the ethnobotanical use of N. sativa seed oil as a treatment for diabetes, and suggests potential uses of this product, or compounds derived thereof, against obesity and the metabolic syndrome.
Summary
Introduction
In daily practice in haematology laboratories, spurious increased MCHC induces an analytical alarm and needs prompt corrective action to ensure delivery of the right results to ...the clinicians. The aim of this study was to establish a ‘decision tree’ using the new parameters red blood cells (RBC‐O) and haemoglobin (HGB‐O) from the Sysmex XN‐10 RET obtained by flow cytometry to deliver appropriate results.
Methods
From 128 unknown patients with MCHC > 365 g/L, all erythrocyte parameters including reticulocyte parameters were measured and analysed in parallel with blood smears, chemistry index and osmolarity. Differences between optical parameters (RBC‐O, HGB‐O) and usual parameters (RBC, HGB) obtained by impedance and photometry were reported also.
Results
Four groups were defined from observations: ‐RBC agglutination (n = 22); ‐optical interference (n = 17); ‐RBC disease (n = 18); and ‐others (n = 71). The use of RBC‐O and HGB‐O permitted efficient correction of the abnormalities when RBC agglutination and/or optical interference were present in 36 of 39 patients. Reticulocyte parameters permitted to elaborate an RBC score that allowed a highly sensitive detection of RBC disease patients (17/18).
Conclusion
Based on new parameters, we propose a ‘decision tree’ that delivers time savings and supports biological interpretation in case of elevated MCHC.
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