Immune-related adverse events in the treatment of non-Hodgkin lymphoma with immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0–407) with a median resolution time of 16 days (range 0–98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients’ disease conditions need to be carefully evaluated to decide the optimal management

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004–March 2022) were identified through the high-level term “adrenal cortical hypofunctions”. Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14–201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42–3.04; IC = 0.25, 95%CI = 0.07–0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy

Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same ap- proach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in indi- viduals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hyper- tension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitiv- ity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors

Breakthrough switching speed with an all-optical chalcogenide glass chip: 640 Gbit/s demultiplexing

We report the first demonstration of error-free 640 Gbit/s demultiplexing using the Kerr non-linearity of an only 5 cm long chalcogenide glass waveguide chip. Our approach exploits four-wave mixing by the instantaneous nonlinear response of chalcogenide. Excellent performance is achieved with only 2 dB average power penalty and no indication of error-floor. Characterisation of the FWM efficiency for the chalcogenide waveguide is given and confirms the good performance of the device

New insights into the comorbid conditions of Turner syndrome: results from a long-term monocentric cohort study

Purpose Many questions concerning Turner syndrome (TS) remain unresolved, such as the long-term complications and, therefore, the optimal care setting for adults. The primary aim of this long-term cohort study was to estimate the incidence of comorbid conditions along the life course. Methods A total of 160 Italian patients with TS diagnosed from 1967 to 2010 were regularly and structurally monitored from the diagnosis to December 2019 at the University Hospital of Bologna using a structured multidisciplinary monitoring protocol. Results The study cohort was followed up for a median of 27 years (IQR 12-42). Autoimmune diseases were the comorbid condition with the highest incidence (61.2%), followed by osteoporosis and hypertension (23.8%), type 2 diabetes (16.2%) and tumours (15.1%). Median age of onset ranged from 22 years for autoimmune diseases to 39 years for type 2 diabetes. Malignant tumours were the most prominent type of neoplasm, with a cumulative incidence of 11.9%. Papillary thyroid carcinoma was the most common form of cancer, followed by skin cancer and cancer of the central nervous system. Only one major cardiovascular event (acute aortic dissection) was observed during follow-up. No cases of ischaemic heart disease, heart failure, stroke or death were recorded. Conclusions This cohort study confirms the need for continuous, structured and multidisciplinary lifelong monitoring of TS, thus ensuring the early diagnosis of important comorbid conditions, including cancer, and their appropriate and timely treatment. In addition, these data highlight the need for the increased surveillance of specific types of cancer in TS, including thyroid carcinoma

Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10 126 ), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29\u20137.55; p = 5.1*10 1216 ), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development

A blueprint for a simultaneous test of quantum mechanics and general relativity in a space-based quantum optics experiment

In this paper we propose an experiment designed to observe a general-relativistic effect on single photon interference. The experiment consists of a folded Mach-Zehnder interferometer, with the arms distributed between a single Earth orbiter and a ground station. By compensating for other degrees of freedom and the motion of the orbiter, this setup aims to detect the influence of general relativistic time dilation on a spatially superposed single photon. The proposal details a payload to measure the required effect, along with an extensive feasibility analysis given current technological capabilities