Aplastic anemia secondary to adjuvant Osimertinib therapy: a case report and a review of literature

Aplastic anemia is a rare hematological disorder characterized by suppressed hematopoiesis and pancytopenia. Although several drugs have been associated with aplastic anemia, its occurrence in response to Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is extremely rare. We present a case report of a 63-year-old patient with locally advanced non-small cell lung cancer (NSCLC) who developed aplastic anemia following adjuvant treatment with Osimertinib. Extensive investigations ruled out infectious etiology, and the absence of bone marrow involvement or other identifiable causes suggested a drug-induced etiology, specifically Osimertinib. This case report emphasizes the importance of recognizing this adverse event and considering it as a potential complication of Osimertinib therapy. Vigilant monitoring and prompt management are essential for optimizing patient outcomes. Further studies are needed to better understand the risk factors, underlying mechanisms, and management strategies for Osimertinib-induced aplastic anemia in the adjuvant settings

Rare case of norethisterone-induced hepatitis: A case report.

We report a case of probable norethisterone-related liver injury, manifesting as a significant rise in liver transaminases in a 62-year-old woman. Upon discontinuation of norethisterone, liver transaminases decreased to normal level within two weeks. Knowledge of rare adverse effects of drugs such as norethisterone is necessary for rapid identification and management, especially in patients with risk factors such as non-alcoholic liver disease and obesity

The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare Immune Checkpoint Related Adverse Effects

Immune checkpoint inhibitors (ICIs) are a type of cancer immunotherapy that has provided a tremendous breakthrough in the field of oncology. Currently approved checkpoint inhibitors target the cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed death receptor-1 (PD-1), and programmed death-ligand 1(PD-L1). One of the most known complications of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs). In this chapter, we will focus on selected rare or very rare irAEs, shedding the light on the other side of the coin of personalized cancer immunotherapy. We will also discuss general management approach of irAEs with an in-depth look on each one of these rare irAEs. The chapter will also cover principles of immunotherapy rechallenge post-occurrence of irAEs, and the impact of irAEs incidence on the efficacy of ICI. We will discuss some of the rare or very rare irAEs including cutaneous irAEs, immune-mediated Hypophysitis, hematological irAEs, ophthalmic irAEs, checkpoint inhibitor pneumonitis (CIP), neurologic irAEs, infectious irAEs, and cardiac irAEs. This chapter tried to highlight the significance of identifying emerging rare and very rare irAEs while considering initial assessments and management approaches identified in various clinical practice guideline and primary literature data

Synthesis and in vitro antiproliferative activity of new 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea scaffold-based compounds

A new series of 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea derivatives were synthesized and subjected to in vitro antiproliferative screening against National Cancer Institute (NCI)-60 human cancer cell lines of nine different cancer types. Fourteen compounds 5a-n were synthesized with three different solvent exposure moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure. Substituents with different π and σ values were added on the terminal phenyl group. Compounds 5a-e with a 4-hydroxymethylpiperidine moiety showed broad-spectrum antiproliferative activity with higher mean percentage inhibition values over the 60-cell line panel at 10 µM concentration. Compound 5a elicited lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line. Two compounds, 5a and 5d showed promising mean growth inhibitions and thus were further tested at five-dose mode to determine median inhibitory concentration (IC50) values. The data revealed that urea compounds 5a and 5d are the most active derivatives, with significant efficacies and superior potencies than paclitaxel in 21 different cancer cell lines belonging particularly to renal cancer and melanoma cell lines. Moreover, 5a and 5d had superior potencies than gefitinib in 38 and 34 cancer cell lines, respectively, particularly colon cancer, breast cancer and melanoma cell lines

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele

The Adversarial Robustness of Sampling

Random sampling is a fundamental primitive in modern algorithms, statistics, and machine learning, used as a generic method to obtain a small yet "representative" subset of the data. In this work, we investigate the robustness of sampling against adaptive adversarial attacks in a streaming setting: An adversary sends a stream of elements from a universe $U$ to a sampling algorithm (e.g., Bernoulli sampling or reservoir sampling), with the goal of making the sample "very unrepresentative" of the underlying data stream. The adversary is fully adaptive in the sense that it knows the exact content of the sample at any given point along the stream, and can choose which element to send next accordingly, in an online manner. Well-known results in the static setting indicate that if the full stream is chosen in advance (non-adaptively), then a random sample of size $\Omega(d / \varepsilon^2)$ is an $\varepsilon$-approximation of the full data with good probability, where $d$ is the VC-dimension of the underlying set system $(U,R)$. Does this sample size suffice for robustness against an adaptive adversary? The simplistic answer is \emph{negative}: We demonstrate a set system where a constant sample size (corresponding to VC-dimension $1$) suffices in the static setting, yet an adaptive adversary can make the sample very unrepresentative, as long as the sample size is (strongly) sublinear in the stream length, using a simple and easy-to-implement attack. However, this attack is "theoretical only", requiring the set system size to (essentially) be exponential in the stream length. This is not a coincidence: We show that to make Bernoulli or reservoir sampling robust against adaptive adversaries, the modification required is solely to replace the VC-dimension term $d$ in the sample size with the cardinality term $\log |R|$. This nearly matches the bound imposed by the attack

Early predictors of intensive care unit admission among COVID-19 patients in Qatar

BackgroundCOVID-19 is associated with significant morbidity and mortality. This study aimed to explore the early predictors of intensive care unit (ICU) admission among patients with COVID-19.MethodsThis was a case–control study of adult patients with confirmed COVID-19. Cases were defined as patients admitted to ICU during the period February 29–May 29, 2020. For each case enrolled, one control was matched by age and gender.ResultsA total of 1,560 patients with confirmed COVID-19 were included. Each group included 780 patients with a predominant male gender (89.7%) and a median age of 49 years (interquartile range = 18). Predictors independently associated with ICU admission were cardiovascular disease (adjusted odds ratio (aOR) = 1.64, 95% confidence interval (CI): 1.16–2.32, p = 0.005), diabetes (aOR = 1.52, 95% CI: 1.08–2.13, p = 0.016), obesity (aOR = 1.46, 95% CI: 1.03–2.08, p = 0.034), lymphopenia (aOR = 2.69, 95% CI: 1.80–4.02, p < 0.001), high AST (aOR = 2.59, 95% CI: 1.53–4.36, p < 0.001), high ferritin (aOR = 1.96, 95% CI: 1.40–2.74, p < 0.001), high CRP (aOR = 4.09, 95% CI: 2.81–5.96, p < 0.001), and dyspnea (aOR = 2.50, 95% CI: 1.77–3.54, p < 0.001).ConclusionHaving cardiovascular disease, diabetes, obesity, lymphopenia, dyspnea, and increased AST, ferritin, and CRP were independent predictors for ICU admission in patients with COVID-19

The analysis of gut microbiota in patients with bile acid diarrhoea treated with colesevelam

© 2023 The Authors. Published by Frontiers Media. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3389/fmicb.2023.1134105Introduction: Bile acid diarrhoea (BAD) is a common disorder that results from an increased loss of primary bile acids and can result in a change in microbiome. The aims of this study were to characterise the microbiome in different cohorts of patients with BAD and to determine if treatment with a bile acid sequestrant, colesevelam, can alter the microbiome and improve microbial diversity. Materials and methods: Patients with symptoms of diarrhoea underwent 75-selenium homocholic acid (75SeHCAT) testing and were categorised into four cohorts: idiopathic BAD, post-cholecystectomy BAD, post-operative Crohn’s disease BAD and 75SeHCAT negative control group. Patients with a positive 75SeHCAT (<15%) were given a trial of treatment with colesevelam. Stool samples were collected pre-treatment, 4-weeks, 8-weeks and 6–12 months post-treatment. Faecal 16S ribosomal RNA gene analysis was undertaken. Results: A total of 257 samples were analysed from 134 patients. α-diversity was significantly reduced in patients with BAD and more specifically, in the idiopathic BAD cohort and in patients with severe disease (SeHCAT <5%); p < 0.05. Colesevelam did not alter bacterial α/β-diversity but patients who clinically responded to treatment had a significantly greater abundance of Fusobacteria and Ruminococcus, both of which aid in the conversion of primary to secondary bile acids. Conclusion: This is the first study to examine treatment effects on the microbiome in BAD, which demonstrated a possible association with colesevelam on the microbiome through bile acid modulation in clinical responders. Larger studies are now needed to establish a causal relationship with colesevelam and the inter-crosstalk between bile acids and the microbiome.The research department of MB received project funding from Bowel and Cancer Research for part of this work. The research department of MB received project funding from an unrestricted grant from Tillotts Pharma for part of this work.Published versio

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised