Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.     

Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.     

Remote Continuous Glucose Monitoring With a Computerized Insulin Infusion Protocol for Critically Ill Patients in a COVID-19 Medical ICU: Proof of Concept

OBJECTIVEThe use of remote real-time continuous glucose monitoring (CGM) in the hospital has rapidly emerged to preserve personal protective equipment and reduce potential exposures during coronavirus disease 2019 (COVID-19).RESEARCH DESIGN AND METHODSWe linked a hybrid CGM and point-of-care (POC) glucose testing protocol to a computerized decision support system for continuous insulin infusion and integrated a validation system for sensor glucose values into the electronic health record. We report our proof-of-concept experience in a COVID-19 intensive care unit.RESULTSAll nine patients required mechanical ventilation and corticosteroids. During the protocol, 75.7% of sensor values were within 20% of the reference POC glucose with an associated average reduction in POC of 63%. Mean time in range (70–180 mg/dL) was 71.4 ± 13.9%. Sensor accuracy was impacted by mechanical interferences in four patients.CONCLUSIONSA hybrid protocol integrating real-time CGM and POC is helpful for managing critically ill patients with COVID-19 requiring insulin infusion.     

Protease‐activated receptor‐2 signalling by tissue factor on dendritic cells suppresses antigen‐specific CD4+ T‐cell priming

The precise function of tissue factor (TF) expressed by dendritic cells (DC) is uncertain. As well as initiating thrombin generation it can signal through protease‐activated receptor 2 (PAR‐2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow (BM) ‐derived DC; 20% of BM‐derived DC expressed TF, which did not vary after incubation with lipopolysaccharide (LPS) or dexamethasone (DEX). However, the pro‐coagulant activity of DEX‐treated DC in recalcified plasma was 30‐fold less than LPS‐treated DC. In antigen‐specific and allogeneic T‐cell culture experiments, the TF on DEX‐treated DC provided a signal through PAR‐2, which contributed to the reduced ability of these cells to stimulate CD4⁺ T‐cell proliferation and cytokine production. In vivo, an inhibitory anti‐TF antibody and a PAR‐2 antagonist enhanced antigen‐specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR‐2‐dependent mechanism on DEX‐DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen‐specific CD4⁺ T‐cell activation.     

Accessory mandibular foramina: a CT study of 300 cases

Purpose

The aim of the study was to assess the distribution of accessory foramina in the mandibular body with computed tomography (CT).

Materials and methods

The CT images of the mandibular body in 300 subjects (183 females and 117 males aged between 12 and 85 years) were retrospectively analysed for the presence of accessory foramina. The buccal and lingual surfaces were examined by dividing them into anterior and posterior quadrants.

Results

Of the 300 subjects, 26 presented with accessory foramina on buccal posterior aspect and 70 subjects presented on buccal anterior aspect. Further, on the lingual posterior aspect, 132 subjects presented with accessory foramina and 59 subjects presented on lingual anterior aspect. Most of the subjects with accessory foramina in the buccal posterior, buccal anterior and lingual anterior regions had accessory foramina on other aspects of the mandible as well.

Conclusion

A substantial number of subjects presented with accessory foramina on the lingual posterior aspect when compared to other aspects. Nevertheless, the number of subjects with accessory foramina on other aspects of the mandible was considerable and cannot be ignored. It is suggested that when an accessory foramen is identified in an individual on a particular aspect of the mandibular body, it is highly probable that he will exhibit accessory foramina on other aspects as well.     

Attenuation of Corpus Callosum Axon Myelination and Remyelination in the Absence of Circulating Sex Hormones

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone‐replaced gonadectomized animals were used. These groups were subjected to cuprizone diet‐induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol‐supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo‐treated ovariectomized or intact female levels during remyelination. In castrated males, the non‐aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.     

Internal target volume for post-hysterectomy vaginal recurrences of cervical cancers during image-guided radiotherapy

Objective:

The outcome of post-surgical recurrences of cervical cancer may be improved through radiation dose escalation, which hinges on accurate identification and treatment of the target. The present study quantifies target motion during course of image-guided radiotherapy (IGRT) for vault cancers.

Methods:

All patients underwent planning CT simulation after bladder-filling protocol. A daily pre-treatment megavoltage CT was performed. All translations and rotations were recorded. Post-registration displacement of gross tumour volume (GTV) and centre of mass (COM) of GTV was independently recorded by two observers for fractions one to seven. Day 1 image sets served as reference images against which the displacements of COM were measured. We calculated the displacements of common volume (CV) and encompassing volume (EV) of GTV for both the observers.

Results:

A total of 90 image data sets of 15 patients were available for evaluation. Individual patient GTV and average GTV by both the observers were comparable. The average shifts for EV were 2.4 mm [standard deviation (SD) ±1.2] in the mediolateral, 4.2 mm (SD ±2.8) in the anteroposterior and 4.0 mm (SD ±2.1) in superoinferior directions. Similarly, the average shifts for CV were 1.9 mm (SD ±0.6) in the mediolateral, 3.7 mm (SD ±2.7) in the anteroposterior and 4.4 mm (SD ±2.7) in superoinferior directions. Using Stroom''s/van Herk''s formula, the minimum recommended margins would be 4.5/5.2, 8.2/9.4 and 7.3/8.3 mm, respectively, for lateral, anteroposterior and superoinferior directions.

Conclusion:

Differential directional internal margin is recommended in patients undergoing IGRT for post-surgical recurrence of cervical cancers.

Advances in knowledge:

Internal organ motion of vault cancers can be accounted for by a directional margin to the gross tumour.