Design of a rapid electrochemical biosensor based on MXene/Pt/C nanocomposite and DNA/RNA hybridization for the detection of COVID-19.

Since the rapid spread of the SARS-CoV-2 (2019), the need for early diagnostic techniques to control this pandemic has been highlighted. Diagnostic methods based on virus replication, such as RT-PCR, are exceedingly time-consuming and expensive. As a result, a rapid and accurate electrochemical test which is both available and cost-effective was designed in this study. MXene nanosheets (Ti3C2Tx) and carbon platinum (Pt/C) were employed to amplify the signal of this biosensor upon hybridization reaction of the DNA probe and the virus's specific oligonucleotide target in the RdRp gene region. By the differential pulse voltammetry (DPV) technique, the calibration curve was obtained for the target with varying concentrations ranging from 1 aM to 100 nM. Due to the increase in the concentration of the oligonucleotide target, the signal of DPV increased with a positive slope and a correlation coefficient of 0.9977. Therefore, at least a limit of detection (LOD) was obtained 0.4 aM. Furthermore, the specificity and sensitivity of the sensors were evaluated with 192 clinical samples with positive and negative RT-PCR tests, which revealed 100% accuracy and sensitivity, 97.87% specificity and limit of quantification (LOQ) of 60 copies/mL. Besides, various matrices such as saliva, nasopharyngeal swabs, and serum were assessed for detecting SARS-CoV-2 infection by the developed biosensor, indicating that this biosensor has the potential to be used for rapid Covid-19 test detection.

ECMO Program Quality Improvement Through Educational Resources Amidst Pandemic Staffing Crisis

The COVID-19 pandemic tasked affected healthcare programs to find creative solutions for preserving staff competency amidst high staffing turnover, limited resources, and increased patient acuity. In 2022, our ECMO leadership team aimed to provide additional educational resources to our ECMO specialist team, without adding to the workload of staff burnout. Prior to 2020, our educational structure involved an extensive onboarding process for new ECMO specialists, quarterly hands-on drill simulations, and a yearly recertification exam. From 2020 to 2021, we saw a significant amount of turnover within our ECMO department amidst the pandemic. We ended 2020 with 36 specialists and 2021 with 18 specialists, hiring 12 new specialists. Our ECMO census continued to increase with 72 total runs and average daily census of 2.2 in 2021, up to 99 total runs and average daily census of 2.4 in 2022. 2021 ELSO data showed that 60% of our patient runs contained mechanical errors including air entrainment, cannula problems, circuit exchanges, oxygenator failure, and thrombosis. In order to support our staff with so many new specialists who are expected to care for a higher quantity of patients with more complex morbidities, at the same exceptional quality as our most senior staff, we provided a variety of additional educational resources in 2022. Visual aids were created for our 3 ECMO pumps including pump physiology, basic handling skills, emergencies, and advanced scenarios. We also created a pocket guide combining the educational information taught in the onboarding class with other various resources provided to our staff. ECMO staff members can keep the pocket guide to reference, and to add their own notes as needed. Lastly, a monthly newsletter sent to our staff, containing programmatic updates, educational tips and quizzes, reminders, and helpful links. After surveying our specialists at the end of 2022, we found that >80% of the specialists watch the videos before or during shifts, 100% watch the videos to prepare for water drills, and >80% own a pocket guide. 75% found the additional resources helpful to succeed in water drills and staying prepared to sit pump. Our 2022 ELSO data also showed a decrease to 43% of patient runs containing mechanical errors. MUSC is ELSO-designated platinum-level for both the pediatric and adult ECMO program, signifying the highest level of performance, innovation, satisfaction, and quality. Our goal is to use current practices combined with mentioned innovative strategies to retain this status in the upcoming year.

Prevalence of adverse drug reactions associated with emergency department visits and risk factors for hospitalization

Objective: Adverse drug reactions increase morbidity and mortality, prolong hospital stay and increase healthcare costs. The primary objective of this study was to determine the prevalence of emergency department visits for adverse drug reactions and to describe their characteristics. The secondary objective was to determine the predictor variables of hospitalization for adverse drug reactions associated with emergency department visits. Method(s): Observational and retrospective study of adverse drug reactions registered in an emergency department, carried out from November 15th to December 15th, 2021. The demographic and clinical characteristics of the patients, the drugs involved and the adverse drug reactions were described. Logistic regression was performed to identify factors related to hospitalization for adverse drug reactions. Result(s): 10,799 patients visited the emergency department and 216 (2%) patients with adverse drug reactions were included. The mean age was 70 +/- 17.5 (18-98) years and 47.7% of the patients were male. A total of 54.6% of patients required hospitalization and 1.6% died from adverse drug reactions. The total number of drugs involved was 315 with 149 different drugs. The pharmacological group corresponding to the nervous system constituted the most representative group (n = 81). High-risk medications, such as antithrombotic agents (n = 53), were the subgroup of medications that caused the most emergency department visits and hospitalization. Acenocumarol (n = 20) was the main drug involved. Gastrointestinal (n = 62) disorders were the most common. Diarrhea (n = 16) was the most frequent adverse drug reaction, while gastrointestinal bleeding (n = 13) caused the highest number of hospitalizations. Charlson comorbidity index behaved as an independent risk factor for hospitalization (aOR 3.24, 95% CI: 1.47-7.13, p = 0.003, in Charlson comorbidity index 4-6;and aOR 20.07, 95% CI: 6.87-58.64, p = 0.000, in Charlson comorbidity index >= 10). Conclusion(s): The prevalence of emergency department visits for adverse drug reactions continues to be a non-negligible health problem. High-risk drugs such as antithrombotic agents were the main therapeutic subgroup involved. Charlson comorbidity index was an independent factor in hospitalization, while gastrointestinal bleeding was the adverse drug reaction with the highest number of hospital admissions.Copyright © 2022 Sociedad Espanola de Farmacia Hospitalaria (S.E.F.H)

Predictors, surrogate and patient-reported outcomes in neoadjuvant immunotherapy for lung cancer: A single-center retrospective study

Background Development of immunotherapy/molecular targeted therapy has significantly increased survival/QoL in advanced stages of NSCLC. Aim(s): to analyze outcome predictors, surrogate outcomes, and PROMs after neoadjuvant immunotherapy for initially unresectable NSCLC. Methods Initially unresectable NSCLC (2014-2021) patients who received immunotherapy +/- platinum-based chemo and/or radiotherapy evaluated after response (reduction of primary tumor and/or mediastinal lymphadenopathy/control of distant metastatic disease underwent surgical resection). PROMs were recorded using EORTC QLQ-29. Results 19 underwent salvage surgery after ICI. 14 had partial response (73.6%), 5 stable disease. Diagnosis was achieved by endobronchial ultrasound (EBUS) in 8 (42.1%), fine-needle aspiration biopsy (FNAB) in 7 (36.8%), metastasis biopsy in 4 (21.0%). 11 (57.9%) were treated with neoadjuvant platinum-based chemo before or with ICI, 1 (5.2%) pemetrexed before ICI, 5 (26.3%) radiotherapy for metastatic control. 3 (15.7%) had ICI adverse effects. Radiotherapy was never used preoperatively for pulmonary/mediastinal disease. 7 (36.8%) received adjuvant therapy (5 [26.3%] pembrolizumab, 1 [5.2%] pemetrexed, 1 [5.2%] pemetrexed + pembrolizumab). 4 (21.0%) had local relapse (no systemic relapse). Median OS was 19 months (range: 2-57.4). At 2 months, 94.7% were alive (6 months: 89.5%;31 months: 79.5%). 2 (10.5%) had local recurrence. 2 (10.5%) died due to recurrence, 1 (5.2%) to COVID. 4 (21.0%) relapsed (median DFS: 5.3 months [range: 2.2-13.0]). PROMs were reviewed retrospectively at 30 days/1 year with significant decrease in coughing, side effects of treatment, surgery-related problems. [Formula presented] Conclusions Radical surgical resections following definitive immunotherapy/immune-chemotherapy in selected initially unresectable NSCLC are feasible and safe (low surgical-related mortality and morbidity). Symptoms and surgery-related outcomes were lower with higher QoL due to a selected group of highly motivated patients. Legal entity responsible for the study The authors. Funding Ministero della Salute. Disclosure All authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Recovery of Platinum and Palladium from Spent Automotive Catalysts: Study of a New Leaching System Using a Complete Factorial Design

The recovery of materials and energy from end-of-life products is increasingly a fundamental factor in the sustainable development of various countries. Recovering metals from different types of waste is not only a practice in support of the environment, but is also a profitable economic activity. For this reason, exhausted automotive catalysts can become renewable sources of critical raw materials such as Pt, Pd, and Rh. However, recovering Pt and Pd from spent catalysts through an efficient, economical, and green method remains a challenge. This article presents a new leaching process for the hydrometallurgical recovery of Pt and Pd from exhausted automotive catalysts. The leaching solution consists of an aqueous mixture of hydrochloric acid, two organic acids (citric acid and acetic acid) and hydrogen peroxide. A complete factorial plan on two levels (2k) was performed in order to evaluate the main effects of the analyzed factors and their interactions. The factors that were presumed to be the most influential on the leaching of Pt and Pd were the concentrations of the different reagents and the reaction time. The optimal circumstances for achieving the largest recovery (over 80% Pt and 100% Pd) were achieved using the following conditions: a concentration of HCl of 5 M, a concentration of H2O2 of 10% wt./vol., a concentration of C2H4O2 of 10%vol./vol., and a reaction time of 3 h.

COVID-19 vaccines in patients with urothelial cancers receiving immune checkpoint inhibitors

Background: COVID-19 vaccination recommendations for cancer patients (pts) are similar to the general population. The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is the occurrence of immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. This retrospective study examined the incidence of severe irAEs in pts with bladder urothelial cancer (UC) treated with CPI therapy who received concurrent vaccinations against Sars-CoV-2. Method(s): Following IRB approval, UC pts who received any approved CPI treatment since FDA authorization of the first COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received 1 or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Result(s): Forty pts were included in our analysis with a median age of 72.5 years (IQR: 66.0-79.2);82% pts were male. At the time of vaccination, 37 pts (92.5%) received CPI monotherapy, 2 pts (5.0%) received combination (combo) CPI therapy, and 1 pt (2.5%) received combo platinum-based chemotherapy and CPI. The vaccine manufacturer was Pfizer Bio-NTech in 22 pts (55.0%), Moderna in 17 pts (42.5%), and Johnson and Johnson in 1 pt (2.5%). Number of vaccinations received was>/= 3 in 27 pts, 2 in 11 pts, and 1 in 2 pts. Six pts (15.0%) experienced severe irAEs following vaccination, including nephritis, colitis, pneumonitis, DKA, and infusion-related reaction. Rates of severe irAEs were 16.2% (6/37) with CPI monotherapy, no severe irAEs occurred in the combo CPI and combo CPI-chemo groups. Severe irAEs occurred after the first vaccine dose in 1 pt (16.7%), second dose in 3 pts (50.0%), and third dose in 2 pts (33.3%) pts. The median time between CPI treatment and vaccination in this group was 22.0 days (IQR: 15.8-36.5. Hospitalization was required for all 6 patients (100%). Three pts (50.0%) required immunosuppressive therapy with a median therapy duration of 64.0 days (IQR 47.0-83.5). Five pts (83.3%) discontinued CPI therapy following severe irAEs. Conclusion(s): In this retrospective study, we observed a 15% rate severe irAE in UC pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI.

Spectral and time-resolved photoluminescence of aromatic amino acids in complex with rhodium and platinum nanoparticles

Thrombus formation issues play an important role in the occurrence, diagnosis and treatment of cardiovascular diseases. The inhibition of platelet aggregation is currently the main therapeutic approach in treatment and prevention of cardiovascular diseases. Understanding the platelet structure and its spectral response to the antiplatelet therapy is the key to personalized medicine today. According to the World Health Organization (WHO) reports, cardiovascular deceases have been remaining the leading cause of death at the global level for the last two decades. The number of deaths has been increased up to nearly 9 million in 2019 [1]. The COVID-19 pandemic has resulted in cardiovascular decease (CVD) increase, which caused deaths in many countries [2-3]. The paper presents studies of the fluorescence intensity of aromatic amino acids namely tyrosine (Tyr) and tryptophan (Trp) in the presence of spherical rhodium and platinum nanoparticles (Rh and Pt NPs). © 2022 SPIE.

Continuous Wavelet Transform of Time-Frequency Analysis Technique to Capture the Dynamic Hedging Ability of Precious Metals

Exploring the hedging ability of precious metals through a novel perspective is crucial for better investment. This investigation applies the wavelet technique to study the complicated correlation between global economic policy uncertainty (GEPU) and the prices of precious metals. The empirical outcomes suggest that GEPU exerts positive influences on the prices of precious metals, indicating that precious metals could hedge against global economic policy uncertainty, which is supported by the inter-temporal capital asset pricing model (ICAPM). Among them, gold is better for long-term investment than silver, which is more suitable for the short run in recent years, while platinum's hedging ability is virtually non-existent after the global trade wars. Conversely, the positive influences from gold price on GEPU underline that the gold market plays a prospective role in the situation of economic policies worldwide, which does not exist in the silver market. Besides, the effects of platinum price on GEPU change from positive to negative, suggesting that the underlying cause of its forward-looking effect on GEPU alters from the investment value to the industrial one. In the context of the increasing instability of global economic policies, the above conclusions could offer significant lessons to both investors and governments.

Forecasting the volatility of precious metals prices with global economic policy uncertainty in pre and during the COVID-19 period: Novel evidence from the GARCH-MIDAS approach

Economic policy is a major determinant of investment and financial decisions;Moreover, prices of precious metals are highly influenced by any uncertainty recorded in the global economic policy. Therefore, the prime consideration of the authors is to assess how global economic policy uncertainty influences the volatility of precious metals prices;particularly "gold, palladium, platinum, and silver” in the pre and during the COVID-19 pandemic. This research analyzed the full sample period (the 1997–2022), pre-COVID period (1997–2019), and during the COVID period (2020−2022) to evaluate the impact during different sample periods. Therefore, the GARCH-MIDAS approach is employed at the data set of different frequencies, i.e., monthly data of GEPU and daily data of precious metals. The results reveal a significant nexus between global GEPU and precious metals price volatility. The findings infer that any uncertainty recorded in global economic policy escalate the price volatility of gold, palladium, platinum, and silver prices. The present study increments the existing literature and provides insights for future scholars, investors, and policymakers. © 2023 Elsevier B.V.

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

Evaluation of the interaction between SARS-CoV-2 spike glycoproteins and the molecularly imprinted polypyrrole

The SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S) was used as a template molecule and polypyrrole (Ppy) was applied as an electro-generated conducting polymer, which was acting as a matrix for the formation of molecular imprints. Two types of Ppy-layers: molecularly imprinted polypyrrole (MIP-Ppy) and non-imprinted polypyrrole (NIP-Ppy) were electrochemically deposited on the working platinum electrode. The performance of electrodes modified by MIP-Ppy and NIP-Ppy layers was evaluated by pulsed amperometric detection (PAD). During the assessment of measurement results registered by PAD, the integrated Cottrell equation (Anson plot) was used to calculate the amount of charge passed through the MIP-Ppy and NIP-Ppy layers. The interaction between SARS-CoV-2 spike glycoproteins and molecularly imprinted polypyrrole (MIP-Ppy) was assessed by the Anson plot based calculations. This assessment reveals that SARS-CoV-2-S glycoproteins are interacting with MIP-Ppy more strongly than with NIP-Ppy. [Display omitted] • The SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S) was molecularly imprinted within polypyrrole (Ppy). • Molecularly imprinted polypyrrole (MIP-Ppy) and non-imprinted polypyrrole (NIP-Ppy) were electro-deposited on Pt electrode. • Performance of electrodes modified by MIP-Ppy and NIP-Ppy was evaluated by pulsed amperometric detection (PAD). • Cottrell equation (Anson plot) was applied for the calculation of passed charge. • Interaction between SARS-CoV-2 protein and MIP-Ppy and NIP-Ppy was evaluated using Anson plot. [ FROM AUTHOR]

Platinum(IV) compounds as potential drugs: a quantitative structure- activity relationship study

Introduction: Machine learning methods, coupled with a tremendous increase in computer power in recent years, are promising tools in modern drug design and drug repurposing.Methods: Machine learning predictive models, publicly available at chemosophia. com, were used to predict the bioactivity of recently synthesized platinum(IV) complexes against different kinds of diseases and medical conditions. Two novel QSAR models based on the BiS algorithm are developed and validated, capable to predict activities against the SARS-CoV virus and its RNA dependent RNA polymerase.Results: The internal predictive power of the QSAR models was tested by 10-fold cross-validation, giving cross-R2 from 0.863 to 0.903. 38 different activities, ranging from antioxidant, antibacterial, and antiviral activities, to potential anti-inflammatory, anti-arrhythmic and anti-malarial activity were predicted for a series of eighteen platinum(IV) complexes.Conclusion: Complexes 1, 3 and 13 have high generalized optimality criteria and are predicted as potential SARS-CoV RNA dependent RNA polymerase inhibitors.

Flexible Label-Free Platinum and Bio-PET-Based Immunosensor for the Detection of SARS-CoV-2.

The demand for new devices that enable the detection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) at a relatively low cost and that are fast and feasible to be used as point-of-care is required overtime on a large scale. In this sense, the use of sustainable materials, for example, the bio-based poly (ethylene terephthalate) (Bio-PET) can be an alternative to current standard diagnostics. In this work, we present a flexible disposable printed electrode based on a platinum thin film on Bio-PET as a substrate for the development of a sensor and immunosensor for the monitoring of COVID-19 biomarkers, by the detection of L-cysteine and the SARS-CoV-2 spike protein, respectively. The electrode was applied in conjunction with 3D printing technology to generate a portable and easy-to-analyze device with a low sample volume. For the L-cysteine determination, chronoamperometry was used, which achieved two linear dynamic ranges (LDR) of 3.98-39.0 µmol L-1 and 39.0-145 µmol L-1, and a limit of detection (LOD) of 0.70 µmol L-1. The detection of the SARS-CoV-2 spike protein was achieved by both square wave voltammetry (SWV) and electrochemical impedance spectroscopy (EIS) by a label-free immunosensor, using potassium ferro-ferricyanide solution as the electrochemical probe. An LDR of 0.70-7.0 and 1.0-30 pmol L-1, with an LOD of 0.70 and 1.0 pmol L-1 were obtained by SWV and EIS, respectively. As a proof of concept, the immunosensor was successfully applied for the detection of the SARS-CoV-2 spike protein in enriched synthetic saliva samples, which demonstrates the potential of using the proposed sensor as an alternative platform for the diagnosis of COVID-19 in the future.

One-step synthesis of triethanolamine-capped Pt nanoparticle for colorimetric and electrochemiluminescent immunoassay of SARS-CoV spike proteins.

Platinum nanoparticles (PtNPs) have been attracted worldwide attention due to their versatile application potentials, especially in the catalyst and sensing fields. Herein, a facile synthetic method of triethanolamine (TEOA)-capped PtNPs (TEOA@PtNP) for electrochemiluminescent (ECL) and colorimetric immunoassay of SARS-CoV spike proteins (SARS-CoV S-protein, a target detection model) is developed. Monodisperse PtNPs with an average diameter of 2.2 nm are prepared by a one-step hydrothermal synthesis method using TEOA as a green reductant and stabilizer. TEOA@PtNPs can be used as a nanocarrier to combine with antigen by the high-affinity antibody, which leads to a remarkable inhibition of electron transfer efficiency and mass transfer processes. On the basis of its peroxidase-like activity and easy-biolabeling property, the TEOA@PtNP can be used to establish a colorimetric immunosensor of SARS-CoV S-protein thought catalyzing the reaction of H2O2 and 3,3',5,5'-tetramethylbenzidine (TMB). Especially, the Ru(bpy)3 2+ ECL reaction is well-achieved with the TEOA@PtNPs due to their great conductivity and loading abundant TEOA co-reactants, resulting in an enhancing ECL signal in immunoassay of SARS-CoV S-protein. As a consequence, two proposed methods could achieve sensitive detection of SARS-CoV S-protein in wide ranges, the colorimetric and ECL detection limits were as low as 8.9 fg /mL and 4.2 fg /mL (S/N = 3), respectively. We believe that the proposed colorimetric and ECL immunosesors with high sensitivity, good reproducibility, and good stability will be a promising candidate for a broad spectrum of applications.

Biogenic metal nanomaterials to combat antimicrobial resistance

Antimicrobial resistance is one of the biggest problems that the healthcare system faces nowadays, with an increasing burden due to the COVID-19 pandemic. Different alternatives to the current treatments of bacterial infections have been studied far away from the use of traditional antibiotics. One of them is nanotechnology, which proposes a suitable solution without the associated problems. Still, the production of different nanomaterials often shows disadvantages, such as producing toxic by-products or the need for functionalization to deliver a suitable therapeutic effect. The implementation of green nanotechnology in nanomaterials synthesis shows great potential, with specific implementation in metal-based nanomaterials. As such, this chapter revised the state of biogenic or biologically produced metal nanoparticles produced by bacteria, fungi, and plant extracts with antimicrobial applications against antibiotic-resistant strains. The chapter summarizes and discusses some of the newest advances in the field to demonstrate that these nanostructures can become a significant enhancement in the fight towards superbugs. © 2022 Elsevier Inc. All rights reserved.

Phase II study of sodium valproate in combination with oral etoposide in platinum-resistant ovarian cancer.

Patients with platinum-resistant ovarian cancer (PROC) have limited therapeutic options and poor survival. There is a need for the development of newer therapies. Sodium valproic acid (VPA) is a short-chain fatty acid histone deacetylase (HDAC) inhibitor with antitumor activity in preclinical models of PROC. Synergism with conventional cytotoxic agents like etoposide has been demonstrated. In this prospective, single-arm, open-label, phase 2 study, we included patients ≥ 18 years with histologically or cytologically confirmed PROC and Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-3. Patients received oral VPA 60 mg/kg/day in three divided doses for 3 days (D1-D3), followed by oral etoposide 50 mg once daily for two consecutive weeks (D4-D17). Serum samples were collected to assess peak VPA drug levels. The primary endpoint was the overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. We sought to show an improvement in response rate from 25% (historically with oral etoposide) to 40% with the addition of VPA. 27 patients were enrolled in the study, and 18 [median age: 52 (45-59) years; serous histology:17 (94%); ECOG-PS 2 or 3: 14 (78%)] were evaluable for the response after 4 months. Nine patients were lost from follow-up before achieving the primary endpoint (mainly due to Covid-related lockdown issues). The median number of prior lines of treatment was 2 (1-3). ORR was 0% according to GCIG criteria. The disease was stable in two patients [clinical benefit rate (CBR) of 11%]. The median OS and PFS were 7 months and 2 months, respectively. Grade ≥ 3 adverse events were reported in 6 (33%) patients. The addition of valproic acid to oral etoposide in patients with PROC and poor general condition was not helpful and failed to improve responses compared to those historically achieved with single-agent etoposide. However, further phase 2 randomized controlled trials with larger sample size can be done to confirm the findings.

Causes of unplanned hospitalizations and factors associated with in-hospital mortality among patients receiving chemotherapy treatment

Background: Hospitalizations during cancer treatment are common, can impact quality of life and the progress of the treatment. We aimed to investigate the main causes of hospitalizations and factors associated with in-hospital mortality for patients receiving chemotherapy. Methods: This retrospective study included patients (pts) with solid tumors, who received outpatient chemotherapy in the 30-day period before unplanned admission to a cancer center in Brazil, from February to December of 2021. Patients with COVID-19 diagnosis were excluded. We retrieved clinical and laboratory data from health records. Logistic regression univariable and multivariable models were performed to analyze the association of the variables and in-hospital mortality as dependent outcome. Results: 784 pts were included, median age at hospitalization was 60 (IQR 49-68), and 57% were female. Most patients had ECOG 0-1 (61%) and nearly 70% had metastatic disease at admission. The most common primary tumors were colorectal (21.6%), breast (20.1%), lung (8.6%), and gastric (8.6%). Over half (56%) received platin-based regimens, usually in association with fluoropyrimidines or taxanes. Pain (33%), nausea (23%) and fever (16%) were the most referred symptoms at admission. The main diagnosis at were infection (32%), followed by disease progression (DP) (29%), and chemotherapy associated toxicity (26%). A total of 174 (22%) pts required intensive care unit support during hospital stay. The in-hospital overall mortality rate was 18%. Univariable analysis revealed poor ECOG-PS, grade 3 anemia, grade 3 thrombocytopenia and DP associated with in-hospital mortality. In the final multivariable model, ECOG ≥ 2 (OR 1.99, CI 95% 1.33 - 2.99, p <0.001), DP (OR 4.62, CI 95% 3.07 - 7.00, p <0.001) and grade 3 anemia (OR 2.38, CI 95% 1.45 - 3.87, p<0.001) remained statistically associated with in-hospital mortality. Conclusions: A substantial percentage of unplanned admissions after chemotherapy treatment are due to toxicity. Poor performance status, progression of disease on admission and severe anemia are associated with worse in-hospital prognosis. Grade 3 anemia on admission was the only toxicity associated with in-hospital mortality. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: R.C. Bonadio: Personal, Expert Testimony: AstraZeneca, Ache;Personal, Research Grant: Novartis;Personal, Roche. All other authors have declared no conflicts of interest.

HER2 copy number variation in non-small cell lung cancer (NSCLC)

Background: The value of increased HER2 gene copy number (GCN) in NSCLC is unclear. In this study we defined its frequency and characterized a cohort of patients harboring it. Methods: Patients with stage IIIB/IV NSCLC enrolled in the Gustave Roussy MSN study (NCT02105168) between Oct. 2009 and Feb. 2016 were screened by FISH (positivity defined as HER2 GCN to centromeres ratio ≥ 2) and tested for other molecular alterations. Descriptive analyses of clinical-pathological data were performed, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: HER2 FISH tested positive in 22 of 250 screened patients (9%). Median age was 60 years (range 47-80), 68% (n=15) were male, 91% (n=20) were current or former tobacco smokers (median exposure 47 pack-year), 64% (n=14) had adenocarcinoma, 18% (n=4) squamous cell and 18% (n=4) large cell carcinoma. 91% (n=20) had an ECOG PS of 0 or 1. Stage IV with extra-thoracic involvement was the most common clinical presentation (64%, n=14). Overall, 95% of patients (n=21) had 1 or 2 metastatic sites at diagnosis (bone 32%, lung 27%, nodes 18%, liver 18%, brain 18%). In 9 patients (41%) 12 concurrent molecular alterations were detected: 5 KRAS mutation (3 G12C, 1 G12D, 1 G61H), 2 HER2 exon 20 insertion, 1 EGFR exon 19 deletion, 1 BRAF V600E mutation, 1 ALK rearrangement, 1 FGFR1 and 1 MET amplification. 18 patients received first-line platinum-based chemotherapy, with 33% (95% CI 16-56) objective response rate and 83% (95% CI 61-94) disease control rate. After a median follow-up of 28 months (95% CI 23-45), median PFS and OS were 5.9 (95% CI 3.4-11.0) and 15.3 (95% CI 10.3-NR) months, respectively. Median PFS was longer in patients with higher GCN. As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions: Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization. Clinical trial identification: NCT02105168. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: M. Tagliamento: Other, Personal, Other, Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly;Other, Personal, Writing Engagements, Honoraria as medical writer: Novartis, Amgen. E. Auclin: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. E. Rouleau: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Amgen, GSK;Financial Interests, Institutional, Invited Speaker: Clovis, BMS;Financial Interests, Institutional, Funding, Data base: AstraZeneca. A. Bayle: Non-Financial Interests, Institutional, Other, Principal/Sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd, Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi;Financial Interests, Institutional, Other, drug supplied: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. D. Planchard: Financial I terests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.

Evaluation of CCR5-Î"32 mutation and HIV-1 surveillance drug-resistance mutations in peripheral blood mononuclear cells of long-term non progressors of HIV-1-infected individuals

Aim: This study aimed to evaluate chemokine receptor 5 delta 32 (CCR5-δ32) mutation and HIV-1 surveillance drug-resistance mutations (SDRMs) in peripheral blood mononuclear cells of long-term non progressors (LTNPs) of HIV-1-infected individuals. Materials & methods: This research was performed on 197 treatment-naive HIV-1-infected patients. After follow-up, it was determined that 15 (7.6%) of these people were LTNPs. The PCR assay was performed to identify the CCR5 genotype and HIV-1 SDRMs. Results: One (6.7%) of the LTNPs was heterozygous (wt/δ32) for the CCR5 delta 32 (CCR5δ32). However, none of the individuals was homozygous for this mutation (δ32/δ32). Moreover, none of the LTNPs showed HIV-1 SDRMs. The CRF35-AD subtype was the most dominant subtype, with a percentage of 93.3%. Conclusion: Iranian elite controllers are negative for CCR5-delta 32 homozygous genotype and drug resistance against antiretroviral drugs.

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Objectives: Immune checkpoint blockade (ICB) has demonstrated efficacy in a small fraction of patients with platinum-resistant ovarian cancer (PROC), some with durable responses. The receptor tyrosine kinase AXL and its sole ligand, GAS6, are possible mediators of T cell exclusion and an attractive target due to the expected synergy between AXL inhibition and immune targeting agents. The recommended phase II dose (RP2D), safety, and efficacy of the combination of AXL inhibition via AVB-S6-500 with durvalumab (MEDI4736) were evaluated in patients with PROC. Methods: In this open-label Phase Ib open-label study, patients with PROC received AVB-S6-500 and durvalumab therapy in escalating dosing regimens guided by a Bayesian optimal interval (BOIN) design: durvalumab (1500 mg Q4W) and AVB-S6-500 (10mg/kg Q2W, 15mg/kg Q2W, 20mg/kg Q2W) with durvalumab infused prior to AVB-S6-500. The response was evaluated using modified RECIST v1.1. Pharmacokinetic/pharmacodynamic (PK/PD) studies were collected, and PD-L1 status and tumor/tumor microenvironment AXL and GAS6 staining pre and on-treatment were assessed. Results: Eleven patients with epithelial ovarian cancer (six clear cells [55%], four high-grade serous [36%], one endometrioid histology [1%]) received treatment per protocol. The median number of prior lines of therapy was 3 (range: 1-5);73% (8/11) of patients had received prior bevacizumab. There were no DLTs noted over the 6-week period and no grade ≥3 adverse events attributed to study drugs. Five patients experienced an immune-related AE, most commonly liver enzyme elevations (36%). Infusion reaction with AVB-S6- 500 was noted in the first two subjects, prompting the institution of a premedication regimen, after which only one of the nine additional patients experienced an infusion reaction. Dose delays greater than one week occurred in six (55%) patients;three patients experienced delays for cancer-related complications (small bowel obstruction, pneumonia, severe fatigue), while three patients experienced delays for non-medical causes (COVID/travel, weather). Patients received therapy for a median of two cycles (range: 1-6), and there were no responses noted across all dosing levels. One patient had stable disease, with a duration of response of three months. Only two patients had strong (2+) AXLstaining on pretreatment biopsy, both with high-grade serous histology. The majority of serum AXL levels were within previously demonstrated ranges (range: 5.6-112ng/mL), though two patients had comparatively high levels (102, 112ng/mL). PK/PD analysis revealed expected AVB-S6-500 levels at initial postdose (C1D1), but low levels at trough (C2D1 predose) when compared to prior AVB-S6-500 data [1]. Conclusions: The combination of AVB-S6-500 and durvalumab was tolerable in this PROC patient population at all dosing levels tested. Exploratory studies to correlate lack of response to AXL-GAS6 pathway alterations, tumor microenvironment, and clinical characteristics, such as prior treatment, dosing delays, burden of disease, and ascites, are ongoing.