Nonclinical Safety, Pharmacokinetics, and Pharmacodynamics of Atacicept

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G1 Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating–inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t1/2 of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations >99%, and circulating mature B-cell concentrations up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development

Prediction of early distant recurrence in upfront resectable pancreatic adenocarcinoma: A multidisciplinary, machine learning-based approach

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients were retrospectively enrolled. Preoperative clinical and radiological (CT-based) data were systematically evaluated; moreover, 182 radiomics features (RFs) were extracted. Most significant RFs were selected using minimum redundancy, robustness against delineation uncertainty and an original machine learning bootstrap-based method. Patients were split into training (n = 94) and validation cohort (n = 53). Multivariable Cox regression analysis was first applied on the training cohort; the resulting prognostic index was then tested in the validation cohort. Clinical (serum level of CA19.9), radiological (necrosis), and radiomic (SurfAreaToVolumeRatio) features were significantly associated with the early resurge of distant recurrence. The model combining these three variables performed well in the training cohort (p = 0.0015,HR = 3.58,95%CI = 1.98–6.71) and was then confirmed in the validation cohort (p = 0.0178,HR = 5.06,95%CI = 1.75–14.58). The comparison of survival curves between low and high-risk patients showed a p-value <0.0001. Our model may help to better define resectability status, thus providing an actual aid for pancreatic adenocarcinoma patients’ management (upfront surgery vs. neoadjuvant chemotherapy). Independent validations are warranted

Guidelines on the diagnosis, treatment and management of visceral and renal arteries aneurysms: a joint assessment by the Italian Societies of Vascular and Endovascular Surgery (SICVE) and Medical and Interventional Radiology (SIRM)

: The objective of these Guidelines is to provide recommendations for the classification, indication, treatment and management of patients suffering from aneurysmal pathology of the visceral and renal arteries. The methodology applied was the GRADE-SIGN version, and followed the instructions of the AGREE quality of reporting checklist. Clinical questions, structured according to the PICO (Population, Intervention, Comparator, Outcome) model, were formulated, and systematic literature reviews were carried out according to them. Selected articles were evaluated through specific methodological checklists. Considered Judgments were compiled for each clinical question in which the characteristics of the body of available evidence were evaluated in order to establish recommendations. Overall, 79 clinical practice recommendations were proposed. Indications for treatment and therapeutic options were discussed for each arterial district, as well as follow-up and medical management, in both candidate patients for conservative therapy and patients who underwent treatment. The recommendations provided by these guidelines simplify and improve decision-making processes and diagnostic-therapeutic pathways of patients with visceral and renal arteries aneurysms. Their widespread use is recommended

Radiological imaging and non-surgical local treatments for cholangiocarcinoma

Cholangiocarcinoma (CC) is a malignancy with a very heterogeneous spectrum of morphopathological and prognostic characteristics. Diagnostic imaging is fundamental for early detection, preoperative staging, and resectability assessment, as well as early recognition of prognostic factors. Radical surgical treatment is limited by disease stage and technical feasibility. Interventional radiology has acquired a critical function in addressing disease control and survival improvement through loco-regional therapies, specifically in the setting of intrahepatic CC. In this review, we will describe the current state of art of diagnostic imaging, focusing on intrahepatic CC and proximal extrahepatic CC, and delineate the available loco-regional therapies strategies for unresectable intrahepatic CC

Biologic Data of Cynomolgus Monkeys Maintained under Laboratory Conditions

<div><p>The cynomolgus monkey (<i>Macaca fascicularis</i>) is a well-known non-human primate species commonly used in non-clinical research. It is important to know basal clinical pathology parameters in order to have a reference for evaluating any potential treatment-induced effects, maintaining health status among animals and, if needed, evaluating correct substantiative therapies. In this study, data from 238 untreated cynomolgus monkeys (119 males and 119 females of juvenile age, 2.5 to 3.5 years) kept under laboratory conditions were used to build up a reference database of clinical pathology parameters. Twenty-two hematology markers, 24 clinical chemistry markers and two blood coagulation parameters were analyzed. Gender-related differences were evaluated using statistical analyses. To assess the possible effects of stress induced by housing or handling involved in treatment procedures, 78 animals (35 males and 35 females out of 238 juvenile monkeys and four adult males and four adult females) were used to evaluate cortisol, corticosterone and behavioral assessment over time. Data were analyzed using a non-parametric statistical test and machine learning approaches. Reference clinical pathology data obtained from untreated animals may be extremely useful for investigators employing cynomolgus monkeys as a test system for non-clinical safety studies.</p></div

For each time point, it is showed a number of rows equal to the comparison between the categories considered.

<p>Each row shows the category considered (left), the bar plot reporting the p-value computed by the Chi-square test (center) for each parameter and the percentage of accuracy obtained by the classification algorithm (right). Only the results associated with a p-value < 0.05 were considered.</p

Set of hematological and biochemical measurements significantly different between female and male in Cohort 1.

<p>Each measurement corresponds to four columns: the average value and the standard deviation for females (i) and males (ii), (iii) log2 Fold Change (FC) of the measurements computed as females versus males (both represented as heat maps), and (iv) the p-values computed by Wilcoxon Rank-Sum test.</p

Box plots reporting cortisol and corticosteone values at each time point for each study, Panel A and B respectively.

<p>in Panel C Line plot reporting the average level of cortisol and corticosterone for each time point. The statistical significance of the comparison with respect to T-3 time point is reported. *** p-value < 0.0001, ** p-value < 0.01, * p-value < 0.05; Wilcoxon Rank-Sum test.</p

Description of the studies.

<p>Panel A reports the features of <b>Cohort 1</b> and <b>Cohort 2</b> in terms of number of animals, age, sex and housing condition. Panel B reports the features of animals in <b>Cohort 2</b>, grouped by the study to which they belong. Panel C shows a Venn diagram showing overlapping of animals in <b>Cohort 1</b> and <b>Cohort 2</b>. Panel D summarizes the experimental design used to collect biological samples at different time points. The star symbol represents the placebo treatment performed. Note that on Day 8 before the intravenous or subcutaneous administration of the physiological solution, was collected the blood and urine samples. S = Study, IV = IntraVenous infusion, SC = SubCutaneous injection.</p