Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor,pexidartinib

Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0–8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) μg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2–4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL). Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.     

Pancreatic acinar cell carcinoma: A comprehensive review

Acinar cell carcinoma (ACC) is a rare pancreatic malignancy with distinctive clinical, molecular, and morphological features. The long-term survival of ACC patients is substantially superior to that of pancreatic adenocarcinoma patients. As there are no significant patient series about ACCs, our understanding of this illness is mainly based on case reports and limited patient series. Surgical resection is the treatment of choice for patients with the disease restricted to one organ; however, with recent breakthroughs in precision medicine, medicines targeting the one-of-a-kind molecular profile of ACC are on the horizon. There are no standard treatment protocols available for people in which a total surgical resection to cure the condition is not possible. As a result of shared genetic alterations, ACCs are chemosensitive to agents with activity against pancreatic adenocarcinomas and colorectal carcinomas. The role of neoadjuvant or adjuvant chemoradiotherapy has not been established. This article aims to do a comprehensive literature study and present the most recent information on acinar cell cancer.     

Screening for Candida auris in patients admitted to eight intensive care units in England, 2017 to 2018

Background Candida auris is an emerging multidrug-resistant fungal pathogen associated with bloodstream, wound and other infections, especially in critically ill patients. C. auris carriage is persistent and is difficult to eradicate from the hospital environment.AimWe aimed to pilot admission screening for C. auris in intensive care units (ICUs) in England to estimate prevalence in the ICU population and to inform public health guidance.MethodsBetween May 2017 and April 2018, we screened admissions to eight adult ICUs in hospitals with no previous cases of C. auris, in three major cities. Swabs were taken from the nose, throat, axilla, groin, perineum, rectum and catheter urine, then cultured and identified using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Patient records were linked to routine ICU data to describe and compare the demographic and health indicators of the screened cohort with a national cohort of ICU patients admitted between 2016 and 2017.ResultsAll C. auris screens for 921 adults from 998 admissions were negative. The upper confidence limit of the pooled prevalence across all sites was 0.4%. Comparison of the screened cohort with the national cohort showed it was broadly similar to the national cohort with respect to demographics and co-morbidities.ConclusionThese findings imply that C. auris colonisation among patients admitted to ICUs in England is currently rare. We would not currently recommend widespread screening for C. auris in ICUs in England. Hospitals should continue to screen high-risk individuals based on local risk assessment.     

Pain after posterolateral versus nerve-sparing thoracotomy: A randomized trial

Objectives

Post-thoracotomy pain leads to patient discomfort, pulmonary complications, and increased analgesic use. Intercostal nerve injury during thoracotomy or its entrapment during closure can contribute to post-thoracotomy pain. We hypothesized that a modified technique of posterolateral thoracotomy and closure, preserving the intercostal neurovascular bundle, would reduce acute and chronic post-thoracotomy pain.

Management of pediatric differentiated thyroid cancer: An overview for the pediatric oncologist

Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.     

The response of Prorocentrum sigmoides and its associated culturable bacteria to metals and organic pollutants

This study investigates the effect of metals (cadmium, lead, mercury, and tellurium) and organic pollutants (benzene, diesel, lindane, and xylene) on a dinoflagellate—Prorocentrum sigmoides Böhm—and its associated culturable bacteria. Two bacterial cultures (Bacillus subtilis strain PD005 and B. xiamensis strain PD006) were isolated from P. sigmoides and characterized by scanning electron microscopy, 16S ribosomal RNA sequencing, biochemical analyses, and growth curve studies. This study points to a mutualistic relationship between P. sigmoides and its associated Bacillus isolates. P. sigmoides enhanced the growth of its associated Bacillus spp., through the secretion of extracellular exudates. In return, both Bacillus isolates contributed to the resistance of P. sigmoides to metals and organic pollutants. P. sigmoides and both Bacillus isolates exhibited concentration‐dependent responses to metals and organic pollutants. An intriguing feature was the similar response of P. sigmoides and its associated Bacillus isolates to mercury and cadmium, indicating a co‐selection of mercury and cadmium resistance. This provides support to the “dinoflagellate host‐phycosphere bacteria” behaving as a single functional unit. However, the sensitivity profiles of P. sigmoides and its associated Bacillus isolates are different with respect to metals versus organic pollutants. These aspects need to be addressed in future studies to unravel the effect of metal and organic pollutants on dinoflagellates, an important component of the phytoplankton community, and to discern the influence of associated “phycosphere” bacteria on the response of dinoflagellates to pollutants.