Reinfection with SARS‐CoV‐2 in general population,

alexandrossfakianakis shared this article with you from Inoreader Reinfection with SARS‐CoV‐2 in general population, South Korea; nationwide retrospective cohort study via Journal of Medical Virology Abstract To better understand epidemiology of SARS-CoV-2 reinfections, we analyzed national data from South Korea n who were followed longitudinally from January 2020 to April 2022. We conducted a nationwide retrospective cohort study to estimate possible SARS-CoV-2 reinfection rates in all residents in South Korea, with at least two episodes of laboratory-confirmed SARS-CoV-2 infection by reverse-transcriptase polymerase chain reaction (RT-PCR) or rapid antigen test (RAT) performed at least 45 or more days between both episodes, between January 2020 and April 2022. There were 1,6130,855 laboratory-confirmed SARS-CoV-2 cases in South Korea, with 55,841 (346.2 per 100,000; or 0.3% of all infections) were cases of possible reinfections. Reinfection rate has increased from 6.0 cases per 100,000 during Pre-Delta period to 128.0 cases per 100,000 and 355.1 cases per 100,000 during Delta and Omicron periods, respectively. Persons with one dose of vaccination had the highes t reinfection rate of 642.2 per 100,000, followed by unvaccinated persons (536.2/100,000) and two-dose vaccinated persons (406.3/100,000). Our finding suggests the majority of possible reinfections occurred following emergence of new variants. This article is protected by copyright. All rights reserved. View on Web

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Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma

alexandrossfakianakis shared this article with you from Inoreader Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma via Annals of Surgery - Most Popular Articles Objective: To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing. Summary of background data: Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC. Methods: Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance. Results: Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93–20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse. Conclusions: Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease. View on Web

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Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy

alexandrossfakianakis shared this article with you from Inoreader Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy via Pediatric Blood & Cancer Abstract Background l-Asparaginase hydrolyzes l-asparagine and not its enantiomer d-asparagine. Unlike l-asparagine, d-asparagine is nonessential for the survival of acute lymphoblastic leukemia (ALL) cells. Studies showed that serum asparagine is depleted below 0.5 μM in ≥96% of the patients during pegylated Escherichia coli l-asparaginase (PEGasparaginase) treatment; however, cerebrospinal fluid (CSF) asparagine levels are depleted in only 20%–30% of the patients. Thus far, studies only reported the total CSF asparagine (sum of d- and l-asparagine) concentrations. Data on the pharmacological goal, which is l-asparagine depletion, are lacking. Method Therefore, we studied this in 30 patients (95 samples) with newly diagnosed ALL. They received two doses of PEGasparaginase on day 4 and 18 in induction. Results Median age at diagnosis was 5.7 years (range 1.5–17.1 years). d-Asparagine and l-asparagine concentrations (median (range)) before PEGasparaginase treatment were 0.038 (0.0–0.103) μM and 6.1 (1.82–11.5) μM, respectively. CSF l-asparagine concentrations were reduced by 85% (76%–100%) and approximately one-third of the patients (32%) had CSF l-asparagine depletion below 0.5 μM 11 days after the second PEGasparaginase dose administration. CSF d-asparagine and l-glutamine levels remained stable before and after administration of PEGasparaginase. The percentage of d-asparagine as a fraction of total asparagine (sum of d- and l-asparagine) was 0.62% before and 4.5% after PEGasparaginase treatment. No correlation was found between higher serum PEGasparaginase activity and CSF l-asparagine concentration. Conclusion l-Asparagine is not a better parameter than total asparagine in CSF due to the negligible amount of d-asparagine in the CSF before and after PEGasparaginase treatment. View on Web

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Lifetime exposure to welding fume and risk of some rare cancers

alexandrossfakianakis shared this article with you from Inoreader Lifetime exposure to welding fume and risk of some rare cancers via American Journal of Epidemiology - Advance Access Abstract We investigated the association between exposure to welding fumes and the risk of biliary tract, male breast, bone, thymus cancer, cancer of the small intestine, eye melanoma, and mycosis fungoides among males in a European, multi-center case–control study. From 1995 to 1997, 644 cases and 1,959 control subjects from seven countries were studied with respect to information on welding and potential confounders. We linked the welding histories of the participants with a m easurement-based exposure matrix to calculate lifetime exposure to welding fumes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models, conditional on country and 5-year age groups, and adjusted for education and relevant confounders. Regular welding was associated with an increased risk of cancer of the small intestine (OR 2.30, CI 1.17, 4.50). Lifetime exposure to welding fumes above the median of exposed controls was associated with an increased risk of cancer of the small intestine (OR 2.00, CI 1.07, 3.72) and male breast (OR 2.07, CI 1.14, 3.77), and some elevation in risk was apparent for bone cancer (OR 1.92, CI 0.85, 4.34) with increasing lifetime exposure to welding fumes. Welding fumes could contribute to an increased risk of some rare cancers. View on Web

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Analyzing Longitudinally Collected Viral Load Measurements in Youth With Perinatally-Acquired HIV Infection: Problems and Possible Remedies

alexandrossfakianakis shared this article with you from Inoreader Analyzing Longitudinally Collected Viral Load Measurements in Youth With Perinatally-Acquired HIV Infection: Problems and Possible Remedies via American Journal of Epidemiology - Advance Access Abstract HIV viral load (VL) is an important quantitative marker of disease progression and treatment response in people living with HIV infection (PLHIV), including children with perinatally-acquired HIV. Measures of VL are often used to predict different outcomes of interest in this population such as HIV-associated neurocognitive disorder. One popular approach to summarizing historical viral burden is the area under a time-VL curve (AUC). However, alternative historical VL summ aries (HVSs) may better answer the research question of interest. In this manuscript, we discuss and contrast AUC with alternative HVSs including the time-averaged AUC, duration of viremia, percent time with suppressed VL, peak VL, and age at peak VL. Using data on youth with perinatally-acquired HIV infection from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP), we show that HVSs and their associations with full scale IQ depend on when the viral loads were measured. When viral load measurements are incomplete, as can be the case in observational studies, analysis results may be subject selection bias. To alleviate bias we detail an imputation strategy and we present a simulation study demonstrating that unbiased estimation of a historical VL summary is possible with a correctly specified imputation model. View on Web

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The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models

alexandrossfakianakis shared this article with you from Inoreader The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models via Neuro-Oncology Advance Access Abstract Background Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Results Ulix ertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. Conclusions These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned int ernational phase I/II umbrella trial. View on Web

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