Outcomes of relapsed/refractory extracranial germ cell tumors treated on conventional salvage chemotherapy without stem cell rescue: Experience from a tertiary cancer center

alexandrossfakianakis shared this article with you from Inoreader Outcomes of relapsed/refractory extracranial germ cell tumors treated on conventional salvage chemotherapy without stem cell rescue: Experience from a tertiary cancer center via Pediatric Blood & Cancer Abstract Background and aims Data on the outcome and prognostic indicators in extracranial relapsed/refractory germ cell tumors (rel/ref-GCTs) in children are limited to a few studies. This study looks at remission rates and outcomes of rel/ref-GCTs treated with conventional salvage chemotherapy (SC) regimens without stem cell rescue at a single center in the developing world. Methods Patients treated at our center from January 2009 to December 2018 were included. Risk at primary presentation was stratified as all completely excised teratomas and stage I gonadal tumors being low risk (LR); stage IV ovarian, stage III–IV extragonadal GCTs as high risk (HR), and the remaining as intermediate risk (IR). SC regimens were: vinblastine–ifosfamide–cisplatin/carboplatin or paclitaxel–ifosfamide–cisplatin/carboplatin, or cisplatin/carboplatin–etoposide–bleomycin. Local therapy was either surgery and/or radiotherapy. Results The analyzable cohort comprised 50 patients (44 = rel-GCTs; 6 = ref-GCTs) with a median age of 3.8 years and male:female ratio of 1.27:1. Primary location was ovary in 16 (32%), testicular in 10 (20%), and extragonadal in the rest (48%). Local, metastatic, and combined progression was noted in 28 (56%), 14 (28%), and eight (16%) patients, respectively, at a median time of 8.5 months. At a median follow-up of 60 months, the 5-year event-free survival (EFS) and overall survival (OS) of the entire cohort (n = 50) were 42.4% and 50.0%, respectively. In patients previously exposed to platinum analogs (n = 38), 5-year-EFS and OS were 27.7% and 31.7%, respectively. Local relapses did better when compared to metastatic and combined relapses (5-year EFS: 64% vs. 23% vs. 0%; p = .009). LR and IR tumors did better compared to HR (5-year EFS: 81.5% vs. 49.3% vs. 6.5%; p = .002). Patients with normalization of t umor markers after two cycles had a superior EFS (57.6% vs. 0%; p < .001). Relapsed tumors fared better than primary refractory GCTs (5-year EFS: 48.6% vs. 0%; p < .001). Conclusions Primary refractory GCTs, extragonadal rel-GCTs, and rel/ref-GCTs with a poor biochemical response did poorly with conventional SC and need alternative treatment strategies. The rel/ref-testicular GCTs had the best chance of salvage despite a second recurrence (5-year EFS and OS: 28.60% and 42.90%, respectively). View on Web

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Genomic profiling and precision medicine in complex ameloblastoma

alexandrossfakianakis shared this article with you from Inoreader Genomic profiling and precision medicine in complex ameloblastoma via Head & Neck Abstract Background Ameloblastoma may present a significant treatment challenge in the locally advanced, recurrent and metastatic setting. Comprehensive genomic profiling (CGP) can identify targetable genomic alterations to aid in treatment. Methods Ameloblastoma samples were sequenced using hybrid-capture based sequencing. A systematic literature review was performed to examine outcomes in studies employing targeted treatment in ameloblastoma. Results We reviewed 14 cases of Ameloblastoma using CGP. There were six patients with activating BRAF mutations, five with PIK3CA, five with SMO, four with FGFR2, one with EGFR, and one with ROS1. All cases were MSI stable and the median TMB was 2.5 mutations/Mb. A separate literature review of clinical outcomes in ameloblastoma showed a predominance of at least partial response to targeted treatment (7/12 cases). Conclusion CGP is helpful in identifying specific driver mutations in patients with complex ameloblastoma. Targeted treatment has been employed with success in achieving treatment response. View on Web

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Exogenous fetuin‐A protects against sepsis‐induced myocardial injury by inhibiting oxidative stress and inflammation in mice

alexandrossfakianakis shared this article with you from Inoreader Exogenous fetuin‐A protects against sepsis‐induced myocardial injury by inhibiting oxidative stress and inflammation in mice via Fundamental & Clinical Pharmacology Abstract Sepsis-induced myocardial injury is a consequence of septicemia and is one of the major causes of death in intensive care units. A serum glycoprotein called fetuin-A is secreted largely by the liver, tongue, placenta, and adipose tissue. Fetuin-A has a variety of biological and pharmacological properties. The anti-inflammatory and antioxidant glycoprotein fetuin-A has shown its efficacy in a number of inflammatory disorders including sepsis. However, its protective role against sepsis-induced myocardial injury remains elusive. The purpose of this work is to explore the role of fetuin-A in mouse models of myocardial injury brought on by cecal ligation and puncture (CLP). CLP significantly induced the myocardial injury assessed in terms of elevated myocardial markers (serum CK-MB, cTnI levels), inflammatory markers (IL-6, TNF-α) in the serum, and oxidative stress markers (increased MDA levels and decreased reduced glutathione) in heart tissue homogenate following 24 hours of ligati on and puncture. Further, hematoxylin and eosin (H&E) staining showed considerable histological alterations in the myocardial tissue of sepsis-developed mice. Interestingly, fetuin-A pretreatment (50 and 100 mg/kg) for four days before the CLP procedure significantly improved the myocardial injury and was evaluated in perspective of a reduction in the CK-MB, cTnI levels, IL-6, and TNF-α in sepsis-developed animals. Fetuin-A pretreatment significantly attenuated the oxidative stress and improved the myocardial morphology in a dose-dependent manner. The present study provides preliminary evidence that fetuin-A exerts protection against sepsis-induced cardiac dysfunction in vivo via suppression of inflammation and oxidative damage. View on Web

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Cardia and non‐cardia gastric cancer risk associated with Helicobacter pylori in East Asia and the West: A systematic review, meta‐analysis, and estimation of population attributable fraction

alexandrossfakianakis shared this article with you from Inoreader Cardia and non‐cardia gastric cancer risk associated with Helicobacter pylori in East Asia and the West: A systematic review, meta‐analysis, and estimation of population attributable fraction via Helicobacter Abstract Objectives To assess the region-specific relative risk of cardia/non-cardia gastric cancer (CGC/NCGC) associated with Helicobacter pylori (H. pylori) and quantify its contribution to gastric cancer burden using population attributable fraction (PAF). Methods PubMed, EMBASE, Web of Science, and Cochrane Central databases were searched by two reviewers until April 20, 2022. The association between H. pylori infection and NCGC/CGC was assessed using pooled odds ratios (ORs) with 95% confidence intervals (CIs). PAF was calculated using the formula of H. pylori prevalence and the pooled OR. Results One hundred and eight studies were included. A significant association was observed between H. pylori infection and NCGC in East Asia (OR, 4.36; 95% CI: 3.54–5.37) and the West (OR, 4.03; 95% CI: 2.59–6.27). Regarding CGC, a significant association was found only in East Asia (OR, 2.86; 95% CI: 2.26–3.63), not in the West (OR, 0.80; 95% CI: 0.61–1.05). For studies with a follow-up time of ≥10 years, pooled ORs for NCGC and CGC in East Asia were 5.58 (95% CI: 4.08–7.64) and 3.86 (95% CI: 2.69–5.55), respectively. Pooled OR for NCGC was 6.80 (95% CI: 3.78–12.25) in the West. PAFs showed that H. pylori infection accounted for 71.2% of NCGC, 60.7% of CGC in East Asia, and 73.2% of NCGC in the West. Conclusions Gastric cancer burden associated with H. pylori infection exhibits important geographical differences. Prolonged follow-up period could overcome the underestimation of the magnitude of the association between H. pylori infection and CGC/NCGC. Customized strategies for H. pylori screening and eradication should be implemented to prevent gastric cancer. View on Web

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Addressing adherence to guidelines on prevention of acute chemotherapy‐induced nausea and vomiting in pediatric patients

alexandrossfakianakis shared this article with you from Inoreader Addressing adherence to guidelines on prevention of acute chemotherapy‐induced nausea and vomiting in pediatric patients via Pediatric Blood & Cancer Abstract Background Chemotherapy-induced nausea and vomiting (CINV) is a distressing adverse effect in children receiving cancer treatment. There are evidence-based pediatric clinical practice guidelines (CPG) on chemotherapy emetogenicity and acute CINV prevention, but adherence to these guidelines is low. Procedure A quality improvement-based study was conducted at McMaster Children's Hospital. The SMART aim was to increase adherence to guidelines on prevention of acute CINV in hospitalized patients receiving high (HEC) and moderately emetogenic chemotherapy (MEC) from baseline 25% to more than 70% by June 2021. Barriers were identified by process mapping, and a series of interventions were implemented. Results Guideline adherence was assessed in 270 inpatient chemotherapy administrations (HEC, MEC). Data were collected on 131 charts pre interventions and 139 charts post interventions. Interventions included education, addition of guideline-recommended anti-emetics to the inpatient formulary, and implementation of a standardized CPG tool. Initial rates of total CINV guideline adherence were 25%, which improved to 72% post intervention (p < .001). In subgroup analysis, guideline adherence in the MEC group improved from 13% to 34% (p = .015), and in the HEC group from 32% to 93% (p < .001). The most common reason for nonadherence in the HEC group was failure to use aprepitant as anti-emetic, and in MEC was option for ondansetron monotherapy prophylaxis. Conclusion Using quality improvement methodology, barriers to guideline adherence were identified and interventions implemented. Guideline adherence for prevention of CINV improved, particularly in the HEC group but less for the MEC group. Future steps will include sustainability of interventions and addressing adherence in the MEC group. View on Web

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Periodontitis and low cognitive performance: A population‐based study

alexandrossfakianakis shared this article with you from Inoreader Periodontitis and low cognitive performance: A population‐based study via Journal of Clinical Periodontology Abstract Aim To study the epidemiological association between periodontitis and low cognitive performance amongst older adults, within a representative sample of the US population. Materials and methods Data from 2086 older adults (≥60 years old), representative of 77.1 million people, were retrieved from the NHANES 2011–2014 database. Periodontitis cases were identified and classified according to the AAP/CDC criteria (mild, moderate, and severe). Cognitive function was assessed through the Consortium to Establish a Registry for Alzheimer's disease (CERAD), the Animal Fluency (AFT), the Digit Symbol Substitution (DSST) tests, and the global cognition score. The lowest non-survey weighted quartile for each cognitive test was defined as low cognitive performance. Simple and multiple regression analyses were performed. Results Moderate and severe periodontitis were significantly associated with a low DSST performance (OR = 1.66, and OR = 2.97, respectively). Each millimeter of increase in mean CAL was associated with a lower AFT (OR = 1.44), DSST (OR = 1.86), and global cognition (OR = 1.50) performance. Conclusions The findings of the present study suggest the presence of an independent association between periodontitis and low cognitive performance amongst older adults (≥60 years old). This article is protected by copyright. All rights reserved. View on Web

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Neuroinflammation related to the blood‐brain barrier and sphingosine‐1‐phosphate in a pre‐clinical model of periodontal diseases and depression in rats.

alexandrossfakianakis shared this article with you from Inoreader Neuroinflammation related to the blood‐brain barrier and sphingosine‐1‐phosphate in a pre‐clinical model of periodontal diseases and depression in rats. via Journal of Clinical Periodontology ABSTRACT Aim To explore the potential mechanisms of neuroinflammation (microglia, blood-brain barrier [BBB] permeability, and the sphingosine-1-phosphate [S1P] pathways) resulting from the association between periodontitis and depression in rats. Materials and methods This pre-clinical in vivo experimental study used Wistar rats, in which experimental periodontitis (P) was induced by using oral gavages with Porphyromonas gingivalis and Fusobacterium nucleatum. Then a chronic mild stress (CMS) model was implemented to induce depressive-like behavior, resulting in four groups: P with CMS (P+CMS+), P without CMS (P+CMS-), CMS without P (P-CMS+), and controls (P-CMS-). After harvesting brain samples, Protein/mRNA expression analyses and fluorescence immunohistochemistry were performed in the frontal cortex (FC). Results were analyzed by ANOVA tests. Results CMS exposure increased the number of microglia (an indicator of neuroinflammation) in the FC. In the combined model (P+CMS+), there was a decrease in the expression of tight junction proteins (zonula occludens-1 [ZO-1], occludin) and an increase in intercellular and vascular cell adhesion molecules (ICAM-1, VCAM-1) and matrix metalloproteinase 9 (MMP9), suggesting a more severe disruption of the BBB. The enzymes and receptors of S1P were also differentially regulated. Conclusions Microglia, BBB permeability, and S1P pathways could be relevant mechanisms explaining the association between periodontitis and depression. This article is protected by copyright. All rights reserved. View on Web

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Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial

alexandrossfakianakis shared this article with you from Inoreader Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial via Clinical Infectious Diseases Advance Access Abstract Background Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice daily dolutegravir dosing when co-administered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed HIV-1 RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofov ir-emtricitabine-efavirenz (TEE). Methods We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA<50 copies/mL at week 24. This study was not powered to compare arms. Results 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86%, 95% confidence interval [CI], 75–93%) in the supplementary dolutegravir arm and 53/65 (82%, 95% CI, 70–90%) in the placebo arm had HIV-1 RNA<50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. View on Web

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Pharmacokinetic and pharmacodynamic study of 3 products of epoetin alfa as single subcutaneous dose in healthy volunteers

alexandrossfakianakis shared this article with you from Inoreader Pharmacokinetic and pharmacodynamic study of 3 products of epoetin alfa as single subcutaneous dose in healthy volunteers via Fundamental & Clinical Pharmacology Abstract Background Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980's and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. Objective The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40,000 IU of Eprex/Erypo® and Hemax® PFS. Methods This clinical trial was conceived following an open label, randomized, 3-way 3-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. Results To analyze similarity between Hemax® PFS and the innovator product, Eprex®, AUC and Cmax of both products have been compared. The 90%CI lower limit for the geometric mean ratios was higher than 80% for any comparisons and the 90%CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. Conclusion The comparison between Hemax® PFS and Eprex® resulted in similar 90%CI for Cmax, AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent and elimination (with an elimination half-life close to 25-30 h for each formulation) View on Web

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Myeloid Phenotypes in Tracheostomy‐Associated Granulation Tissue

alexandrossfakianakis shared this article with you from Inoreader Myeloid Phenotypes in Tracheostomy‐Associated Granulation Tissue via The Laryngoscope In patients with indwelling tracheostomy, granulation tissue is a common, recurrent problem that may lead to multiple surgeries, difficulties with decannulation, and even wound contracture leading to stenosis at the site of prosthesis. This study demonstrates that alternatively activated M2 macrophages are increased in airway granulation tissue as determined by gene expression analysis of canonical biomarkers and cell surface antigens assessed by flow cytometry and immunohistochemistry. The monocyte cell populations associated with granulation tissue are predominantly classical subtype and the majority of macrophages were positive for pro-inflammatory marker S100A8/A9 with 36% of macrophages co-localizing the biomarker CD169+, highlighting these cell population as potential therapeutic targets for airway granulation tissue. Objective(s) Tracheostomy-associated granulation tissue is a common, recurrent problem occurring secondary to chronic mucosal irritation. Although granulation tissue is composed of predominantly innate immune cells, the phenotype of monocytes and macrophages in tracheostomy-associated granulation tissue is unknown. This study aims to define the myeloid cell population in granulation tissue secondary to tracheostomy. Methods Granulation tissue biopsies were obtained from 8 patients with tracheostomy secondary to laryngotracheal stenosis. Cell type analysis was performed by flow cytometry and gene expression was measured by quantitative real-time polymerase chain reaction. These methods and immunohistochemistry were used to define the monocyte/macrophage population in granulation tissue and were compared to tracheal autopsy control specimens. Results Flow cytometry demonstrated macrophages (CD45+CD11b+) and monocytes (CD45+FSClowSSClow) represent 23.2 ± 6% of the granulation tissue cell population. The M2 phenotype (CD206) is present in 77 ± 11% of the macrophage population and increased compared to the M1 phenotype (p = 0.012). Classical monocytes (CD45+CD14highCD16low) were increased in granulation tissue compared to controls (61.2 ± 7% and 30 ± 8.5%, p = 0.038). Eighty-five percent of macrophages expressed pro-inflammatory S100A8/A9 and 36 ± 4% of macrophages co-localized CD169, associated with tissue-resident macrophages. M2 gene expression (Arg1/CD206) was increased in granulation tissue (3.7 ± 0.4, p = 0.035 and 3.5 ± 0.5, p = 0.047) whereas M1 gene expression (CD80/CD86) was similar to controls (p = 0.64, p = 0.3). Immunohistochemistry of gra nulation tissue demonstrated increased cells co-localizing CD11b and CD206. Conclusions M2 macrophages are the dominant macrophage phenotype in tracheostomy-associated granulation tissue. The role of this cell type in promoting ongoing inflammation warrants future investigation to identify potential treatments for granulation tissue secondary to tracheostomy. Level of Evidence 3 Laryngoscope, 2023 View on Web

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