Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study

Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 μg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 μg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 μg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.     

Endometriosis-associated ileo-cecal perforation in a woman on the pseudopregnancy regimen

Small intestinal obstruction and perforation associated with endometriosis is uncommon. We report a similar effect following treatment with the combined oral contraceptive. Caution should be exercised when prescribing the combined oral contraceptive in women with suggested small intestinal endometriosis. Disease flare-up after therapy may be associated with intestinal obstruction and perforation.     

A comparison of three urobilinogen tests in trie urine, (the watson,Sparkman, and Wallace and diamond methods) in jaundice and diseases of the liver

The American Journal of Digestive Diseases -     

Factors Associated with Macular Staphyloma Area on Ultra-widefield Fundus Images

PurposeTo assess the feasibility of applying ultra-widefield fundus (UWF) images for macular staphyloma area (MSA) measurement and investigate the associated factors with MSA.MethodsThis is a retrospective study. MSA was measured by UWF imaging. Central foveal thickness, subfoveal choroidal thickness, subfoveal scleral thickness were measured on spectral domain optical coherence tomography. Intraclass correlation coefficients of MSA measurement would be evaluated. Multiple linear regression analysis was used to analyze the associated factors with MSA.ResultsIn total, 135 eyes of 92 patients were enrolled. The mean age was 64.73 ± 10.84 years. Mean MSA on UWF image was 279.67 ± 71.70 mm². Intraclass correlation coefficients of MSA measurement was 0.965 (95% confidence interval [CI], 0.946 to 0.977; p < 0.001). In the multiple linear regression analysis, after adjusting for subfoveal choroidal thickness, best-corrected visual acuity, central foveal thickness, and subfoveal scleral thickness, the factors independently related to MSA were axial length (β = 8.352; 95% CI, 3.306 to 13.398; p = 0.001), sex (β = −26.673; 95% CI, −51.759 to −1.586; p = 0.037), age (β = 1.184; 95% CI, 0.020 to 2.348; p = 0.046).ConclusionsIt is feasible to measure MSA on UWF image. Female, longer axial length, and older age may indicate larger MSA.     

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Early SARS-CoV-2 Reinfections within 60 Days and Implications for Retesting Policies

Illustrated by a clinical case supplemented by epidemiologic data, early reinfections with SARS-CoV-2 Omicron BA.1 after infection with Delta variant, and reinfection with Omicron BA.2 after Omicron BA.1 infection, can occur within 60 days, especially in young, unvaccinated persons. The case definition of reinfection, which influences retesting policies, should be reconsidered.     

Pulmonary Function in Scleroderma

Pulmonary function tests were performed in 45 patients with scleroderma. Thirteen patients (29%) were found to have restrictive disease, 12 patients (27%) were found to have obstructive disease, and 19 patients (42%) had small airway disease (SAD). Smoking did not seem to be a factor underlying either obstructive or small airway disease in these patients. A low diffusing capacity was most common in patients with restrictive disease and rarely the only abnormality in pulmonary function. SAD was usually found in patients who had normal chest radiographs and no pulmonary symptoms and was often the only abnormality. SAD is therefore an early and sensitive indicator of pulmonary involvement in scleroderma.