Background Chronic kidney disease patients are at increased risk of mortality with cardiovascular diseases and infections as the two leading causes of death for end-stage kidney disease treated with ...hemodialysis (HD). Mortality from bacterial infections in HD patients is estimated to be 100-1000 times higher than in the healthy population. Methods We comprehensively characterized highly pure circulating neutrophils from HD and healthy donors. Results Protein levels and transcriptome of HD patients' neutrophils indicated massive neutrophil degranulation with a dramatic reduction in reactive oxygen species (ROS) production during an oxidative burst and defective oxidative cellular signaling. Moreover, HD neutrophils exhibit severely impaired ability to generate extracellular NET formation (NETosis) in NADPH oxidase-dependent or independent pathways, reflecting their loss of capacity to kill extracellular bacteria. Ectopic hydrogen peroxidase (H.sub.2O.sub.2) or recombinant human SOD-1 (rSOD-1) partly restores and improves the extent of HD dysfunctional neutrophil NET formation. Conclusions Our report is one of the first singular examples of severe and chronic impairment of NET formation leading to substantial clinical susceptibility to bacteremia that most likely results from the metabolic and environmental milieu typical to HD patients and not by common human genetic deficiencies. In this manner, aberrant gene expression and differential exocytosis of distinct granule populations could reflect the chronic defect in neutrophil functionality and their diminished ability to induce NETosis. Therefore, our findings suggest that targeting NETosis in HD patients may reduce infections, minimize their severity, and decrease the mortality rate from infections in this patient population. Keywords: Neutrophils, Hemodialysis, Infections, Neutrophil degranulation, Neutrophil extracellular traps (NETosis)
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cyclin-dependent kinase (CDK) 4/6 inhibitors given with endocrine therapy are standard of care for the treatment of women with advanced hormone receptor (HR) positive and human epidermal growth ...factor receptor 2 (HER-2) negative breast cancer. Ribociclib is a CDK 4/6 inhibitor with moderate to solid inhibition of CYP3A4, a member of the cytochrome P450 family oxidase system, which may lead to interactions with medicinal substrates that are metabolized via CYP3A4. Statins are among the most widely prescribed medications worldwide, predominantly metabolized by the CYP3A4 isoenzyme. Rhabdomyolysis is a known rare side effect of statins, commonly triggered by drug interactions. We report a case of a 73-year-old woman with metastatic HR-positive and HER-2 negative breast cancer who developed rhabdomyolysis and acute kidney injury due to interaction between simvastatin and ribociclib with a literature review.
Abbreviations CBC Complete blood counts COVID-19 Coronavirus Disease 2019 EOS Eosinophils HB Hemoglobin IgG Immunoglobulin-G LYM Lymphocyte MONO Monocytes NEU Neutrophil PLT Platelet SARS-CoV-2 ...Severe Acute Respiratory Syndrome Coronavirus-2 THC Tetrahydrocannabinol WBC White blood cells Dear Editor On July 29, 2021, the Israeli Ministry of Health approved the third anti-Coronavirus disease 2019(COVID-19) vaccination (3rd-BNT162b2-booster-dose), leading to a sharp daily drop in diagnosed positive COVID-19 cases and mortality rates in Israel 1. ...the groups were: 3rd-BNT162b2-booster-dose low responders (IgG ≤4000 AU/mL) and high responders (IgG > 4000 AU/mL) (Supplementary Table S2). Since low responders may be at higher risk of COVID-19 infection due to the low anti-COVID-19 IgG titers, we tested whether this group was associated with any distinct complete blood count (CBC) features (Supplementary Table S3). Levels of hemoglobin (HB, P = 0.028), neutrophils (Neu, P < 0.042), and monocytes (Mono, P = 0.018) also showed a significant variation but only after the 3rd-BNT162b2-booster-dose (Figure 1C). ...circulating EOS levels may serve as a clinical biomarker predicting IgG response (pre-and post-booster dose), while the other laboratory parameter prediction efficiency may be less clinically relevant when trying to identify individuals at higher risk of severe COVID-19 disease in a pre-vaccinated population. ...our findings imply that patients can keep integrating cannabis during anticancer therapy without any major concern of compromising anti-COVID-19 protective immunity.
BackgroundIn the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without ...reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.MethodsThe double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.ResultsBetween November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.ConclusionIn BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
This study investigates breast cancer survival rates between 2000 and 2022 in northern Israel, focusing on ethnicity, socioeconomic status, age at diagnosis, and the Charlson Comorbidity Index. ...Analyzing data from Clalit Health Services, we studied 8,431 breast cancer patients (6,395 Jewish, 2,036 Arab). We compared five- and ten-year survival rates across different demographics. Ethnicity showed a minor impact on survival (OR 1.12, 95% CI: 0.93 - 1.35). Socioeconomic status had a significant effect, with a higher level of improving survival (OR 2.50, 95% CI: 2.04 - 3.08). Age was crucial; women 18-39 had better survival than 60-100, but no significant difference was found between the 18-39 and 40-59 age groups OR (CI 0.90 - 1.53, p = 0.231). For the Charlson Comorbidity Index, women with scores of 3-10 showed lower survival compared to scores of 0 and 1-2. There was a notable improvement in five-year survival rates among patients aged 18-59 diagnosed from 2009-2018 (90.7%) compared to 2000-2008 (86.9%) (p = 0.0046), but not in patients aged 60-100. The study highlights that socioeconomic status, age, and comorbidity scores are significant in determining survival rates for breast cancer. The improvement in survival rates for younger patients diagnosed more recently reflects advancements in treatment and care. This research provides valuable insights into the factors affecting breast cancer survival rates, underscoring the role of socioeconomic status, age, and comorbidities while also highlighting the progress in breast cancer treatment over recent years.
Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient ...stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.
Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes.
The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage.
Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.
Substantial evidence has accumulated showing that psychological distress affects immune regulation, the response to cancer treatment, and survival. The effect of psychological parameters on the ...effectiveness of immune checkpoint inhibitor (ICI) treatment has not yet been studied. This preliminary study aimed to (a) examine the associations between psychological factors and responses to ICI treatment and (b) assess the associations between psychological factors and blood measures of sPD-1, sCTLA-4, and cytokines that may alter the effect of ICI treatment. The participants were 62 individuals with advanced cancer, aged 18 years or older, who were candidates for ICI treatment as a new line of treatment. The participants answered questionnaires and provided blood samples and medical data prior to the start of ICI treatment and 3 months after. Perceived health status was positively associated with better responses to ICI treatment. In the subsample of participants with biomarkers, worse health-related quality of life was associated with higher IL-6 and sCTLA-4; emotional distress and sleep difficulties were associated with higher sCTLA-4; and better perceived health was associated with lower IL-6 and TNFα. sPD-1 was not associated with psychological measures. This preliminary study found for the first time that some psychological measures could be linked to responses to cancer treatment, possibly via pro-inflammatory cytokines and sCTLA-4.
The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this ...work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment. Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients' disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups. Most outcome measures improved significantly during MC treatment for most patients (
< 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82-157) at baseline to 89 (45-138) at endpoint (-18.98; 95%CI= -26.95 to -11.00;
< 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment. The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.
Introduction
In a previous study, we found that co-administration of proton pump inhibitors (PPIs) with cetuximab was associated with increased skin toxicity. Both these drugs can induce ...hypomagnesemia. The aim of this study was to retrospectively explore the possible influence of PPI drugs on cetuximab skin toxicity and the potential synergistic effect of hypomagnesemia.
Patients and methods
The files of all eligible patients treated with cetuximab during 2015–2016 with metastatic colorectal carcinoma (mCRC) or head and neck (H&N) carcinoma were reviewed. The concomitant use of PPIs was defined if a drug belonging to that class was included in the patient’s chronic medications list.
Results
One hundred eighteen patients (61 with H&N carcinoma, 57 with mCRC) were included in the study, and 58 of the 118 patients received PPIs concomitantly with cetuximab. Skin toxicity of any grade was reported in 33/58 (56.9%) patients on PPIs compared with 22/60 (36.7%) patients (
p
= 0.08) with grade 3–4 in 19/58 (32.8%) and 2/60 (3.3%), respectively (
p
= 0.001). Hypomagnesemia (Mg serum level < 1.2 mg/dL) was reported in 14/58 (25.9%) PPI-treated patients, compared with 5/60 (10.4%) patients not on PPIs (
p
= 0.08). Grade 3–4 skin toxicity or hypomagnesemia (Mg < 0.9 mg/dL) was reported in 23/58 (39.7%) patients on concomitant treatment with PPIs, compared with 3/60 (5%) patients not on PPIs (
p
= 0.001).
Conclusions
Both the rate and the severity of cetuximab-induced skin toxicity and hypomagnesemia were increased by chronic concomitant administration of PPIs. A prospective study is needed to confirm the possible interaction between cetuximab and PPIs.
BackgroundImmune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) can substantially affect patient quality of life and treatment trajectory. Currently, there are no ...reliable pre-treatment biomarkers for predicting the development of irAEs; hence, there is a clinical need for irAE predictive biomarkers.MethodsPlasma samples were obtained at baseline from 426 non-small cell lung cancer (NSCLC) patients treated with ICIs as part of an ongoing multi-center clinical trial (NCT04056247; approved by local IRB committees from each site) with irAE-related information. Proteomic profiling of plasma samples was performed using the SomaScan® assay (SomaLogic Inc.), enabling deep coverage of approximately 7000 proteins in each sample. A machine learning-based model was developed to predict significant irAEs arising up to 3 months from treatment initiation; significant irAEs were defined as irAEs with CTCAE grade ≥3 or irAEs that induced treatment discontinuation. Using the model, we identified a set of plasma proteins, termed Toxicity Associated Proteins (TAPs), that serve as indicators of irAEs depending on their plasma level in the individual patient. Bioinformatic analysis was performed to decipher the biology underlying immune-related toxicity implied by the TAPs.ResultsOverall, 60 patients experienced significant irAEs at early onset; 197 patients had low grade irAEs, irAEs at late onset or AEs that are not immune-related; and 169 patients did not display any adverse event. A computational model was generated to predict significant irAEs, showing a strong correlation between the predicted probability of significant irAEs and the observed rate of such events (R2= 0.92; p-value <0.0001), implying good prediction capabilities. The prediction was based on a set of 449 TAPs. Interestingly, nearly half of these TAPs were previously identified as proteins associated with clinical benefit from ICI therapy, suggesting a close relationship between irAEs and clinical benefit, in accordance with previous reports. A detailed examination of the TAPs revealed some key findings. Patients who experienced irAEs had a larger number of TAPs related to neutrophils, inflammation, and cell death resistance, while the number of lymphocyte-related TAPs was low in these patients. Patients who did not experience irAEs displayed higher levels of extracellular matrix-related proteins.ConclusionsWe describe a novel computational model for predicting significant irAEs in patients with NSCLC based on proteomic profiling of pre-treatment plasma samples. The TAPs provide insights into the biological processes underlying irAEs. Early prediction of irAEs could enable personalized management plans and mitigation strategies to reduce the risk of irAEs in NSCLC.Ethics ApprovalParticipants gave informed consent before taking part. Institutional Review Board of the following institutes gave ethical approval for this work: Asklepios Kliniken GmbH; Rambam Medical Center; Hadassah Hebrew University Medical Center; Meir Medical Center; Emek Medical Center; Kaplan Medical Center; Rabin Medical Center Davidoff Cancer Centre; Shamir Medical Center; Bnai Zion Medical Center; Roswell Park Comprehensive Cancer Center; Asklepios Kliniken GmbH; Sheba Medical Center; Cheltenham General Hospital; Aberdeen Royal Infirmary Grampian NHS; Barzilai Medical Center; Sunderland Royal Hospital; Shrewsbury and Telford Hospital.
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