Busulfan Exposure Target Attainment in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: A Single Day Versus a Multiple Day Therapeutic Drug Monitoring Regimen.

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31, 2014 and November 12, 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1 + 2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval [95% CI]: 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, P < .001). Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Decontamination of a robot used to reprocess reusable surgical instruments.

BACKGROUND: Using robots to handle medical devices in the decontamination area of the Central Sterile Supply Department (CSSD) can reduce risks and address staff shortages. The gripper design must allow reliable cleaning using standard CSSD procedures to avoid build-up of biofilms and possible cross-contamination between different instrument trays and the gripper's functionality. This study explores the design of the robot's gripper regarding cleanability, aiming to determine whether successful cleaning can be achieved even after prolonged drying for a working shift of 8 h. METHODS: We optimized a gripper for cleanability and used it to assess the spread of different test soils depending on different forms of motion. Subsequently, we analysed the cleanability using sheep's blood as test soil, reprocessing the gripper in different assembly configurations after 4 and 8 h of drying, and measuring residual protein. FINDINGS: Based on our investigations, we documented the spread of contamination depending on the type of motion of the gripper's components. Sheep's blood exhibited the highest dispersion among the test soils, permeating through thin crevices. Importantly, all samples displayed residual protein levels below the warning threshold, irrespective of drying time and gripper disassembly or cleaning position. Cleaning in a device-specific optimized position achieved results comparable to cleaning the disassembled individual components. CONCLUSIONS: These findings indicate that cleaning even after one working shift of 8 h and without the labour-intensive disassembly of the gripper is feasible, supporting the future use of robots to handle contaminated medical devices in the CSSD decontamination area.

Age-associated systemic factors change central and peripheral immunity in adult male mice.

Aging coincides with major changes in brain immunity that aid in a decline in neuronal function. Here, we postulate that systemic, pro-aging factors contribute to immunological changes that occur within the brain during aging. To investigate this hypothesis, we comprehensively characterized the central and peripheral immune landscape of 20-month-old male mice using cytometry by time-of-flight (CyTOF) and investigated the role of age-associated circulating factors. We found that CD8+ T cells expressing programmed cell death protein 1 (PD1) and tissue-resident memory CD8+ T cells accumulated in the aged brain while levels of memory T cells rose in the periphery. Injections of plasma derived from 20-month-old mice into 5-month-old receiving mice decreased the frequency of splenic and circulating naïve T cells, increased memory CD8+ T cells, and non-classical, patrolling monocytes in the spleen, and elevated levels of regulatory T cells and non-classical monocytes in the blood. Notably, CD8+ T cells accumulated within white matter areas of plasma-treated mice, which coincided with the expression of vascular cell adhesion molecule 1 (VCAM-1), a mediator of immune cell trafficking, on the brain vasculature. Taken together, we here describe age-related immune cell changes in the mouse brain and circulation and show that age-associated systemic factors induce the expansion of CD8+ T cells in the aged brain.

Lack of embryonic homozygous or adult heterozygous lymphatic phenotypes for a Sos1 mutation and lack of lymphatic embryonic phenotypes for a homozygous Cx47 mutation in mice.

We have studied the lymphatic phenotypes of 2 mutations, known to cause abnormalities of lymphatics in humans, in mice. The Cx47 R260C mutation (variably penetrant in humans heterozygous for it and causing limb lymphedema) had an adult mouse phenotype of hyperplasia and increased lymph nodes only in homozygous condition but we did not find any anatomical phenotype in day 16.5 homozygous embryos. Mice harboring the Sos1 mutation E846K (causing Noonan's in man which occasionally shows lymphatic dysplasia) had no adult heterozygous phenotype in lymphatic vessel appearance and drainage (homozygotes are early embryonic lethals) while day 16.5 heterozygous embryos also had no detectable anatomical phenotype.

Centrifugal Versus Centripetal Origin(s) of the Lymphatic System: Controversy (Mostly) Resolved?

New findings reopen the controversy about centrifugal vs. centripetal origin of the lymphatic system and support that the latter may be the predominant source of lymphatic endothelial cells from mesenchymal lymphangioblasts.

Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin47 R260C point mutation.

Connexin proteins form gap junctions controlling exchange of ions and small molecules between cells and play an important role in movement of lymph within lymphatic vessels. Connexin47 (CX47) is highly expressed in lymphatic endothelial cells and CX47 missense mutations, i.e., R260C, cosegregate with primary lymphedema in humans. However, studies utilizing CX47 knockout mice have failed to demonstrate any lymphatic anomalies. To unravel the lymphatic consequences of expressing a mutant CX47 protein, we used CRISPR technology to create a mouse carrying a Cx47 missense mutation (Cx47R259C) equivalent to the human CX47R260C missense mutation associated with human primary lymphedema. Intradermal Evans Blue dye injection identified a 2-fold increase in regional lymph nodes in homozygous Cx47R259C mice compared to wildtype, particularly in the jugular region (4.8 ± 0.4 and 2.0 ± 0.0, respectively, p<0.01). Associated lymphatic channels were increased in Cx47R259C mice and mesenteric lymph reflux occurred in homozygous Cx47R259C mice but not in wildtype. Contractility of superficial cervical lymphatics, assessed by pressure myography, was reduced in homozygous Cx47R259C mice compared to wildtype. In conclusion, our data are the first to demonstrate a role for the Cx47 protein in lymphatic anatomy and function. This phenotype is similar to that found with other valve deficient mouse mutants, e.g., in Foxc2. Of significance, this study is the first to use CRISPR technology to develop a pre-clinical model of primary lymphedema and demonstrates the importance of distinguishing between lack of and presence of mutant protein when developing clinically relevant animal models for translation of pre-clinical findings.

Imaging of lymphatic dysplasia in Noonan syndrome: Case studies and historical atlas.

To determine the historical use and utility of various lymphatic imaging modalities in Noonan syndrome (NS) patients, we performed a comprehensive literature review by collecting the published medical imaging of NS lymphatic dysplasias. We correlated imaging findings with clinical phenotypes and treatment. Our analysis of lymphatic imaging modalities provides an algorithmic approach to imaging and patient care across the spectrum of NS developmental defects. A total of 54 NS cases have been published since 1975. Using the observations reported in 15 reviewed publications, an association was made between disruptions in central lymphatic flow and poor clinical presentations/outcomes in NS patients.

Human chromosome map of lymphedema-lymphangiogenesis genes: Template for current and future discovery.

We have created a human chromosomal map of the location of known and candidate genes involved in primary lymphedema (PLE). This should facilitate further discovery and provide a basis for understanding microdeletions which cause lymphedema.

SARS-CoV-2/COVID-19, Lymphatic vessels, lymph, and lymphology.

[Editorial] Lymphatic vessels and lymph are a missing link in SARS-CoV-2/COVID-19 pathophysiology and therapeutic strategies. Based on well-established principles of lymphatic function and dysfunction and a neglected literature, this article highlights promising directions for future research and clinical exploration.

Non-contrast MR lymphography of rare lymphatic abnormalities.

Detailed imaging of the lymphatic system often requires direct injection of contrast into lymph nodes which can be technically challenging, time consuming, and produce painful stimuli. We sought to describe the use of non-contrast MR lymphography (NCMRL) for normal controls and patients with a variety of rare disorders associated with lymphatic pathologies. Two control subjects and five affected patients (decompensated Fontan circulation, central conducting lymphatic abnormality, familial lymphedema and two with Gorham-Stout disease) were studied. NCMRL images were segmented in a semiautomated fashion and the major lymphatic channels and thoracic duct (TD) highlighted for identification. Adequate imaging was available for both controls and 4/5 affected patients; the youngest patient could not be imaged given patient motion. For the two controls, the TD was seen in the expected anatomic location. For the decompensated Fontan patient, there were numerous tortuous lymphatic channels, predominantly in the upper chest and neck. For the familial lymphedema patient, a TD was not identified; instead, peripheral lymphatic collaterals near the lateral chest walls. For the first Gorham- Stout patient, the TD was enlarged with large intrathoracic lymph collections. For the second Gorham-Stout patient, there were bilateral TD with lymph collections in vertebral bodies. Using NCMRL, we were able to image normal and abnormal lymphatic systems. An important learning point is the potential need for sedation for younger patients due to long image acquisition times and fine resolution of the structures of interest.

Thoracic duct decompression: An idea whose time has come - again.

[Editorial] Thoracic duct decompression (TDD) is an idea first proposed and applied as a novel therapeutic strategy by lymphologists in the 1960's. TDD is recently being reexamined and, in selected patients with portal hypertension from hepatic cirrhosis or with central venous hypertension from isolated right-sided heart failure, undertaken using advanced surgical and image-guided interventional radiologic approaches.

EVOLUTION OF THE 2020 INTERNATIONAL SOCIETY OF LYMPHOLOGY CONSENSUS DOCUMENT PARALLELS ADVANCES IN LYMPHOLOGY: AN HISTORICAL PERSPECTIVE.

[Editorial] Evolution of the 2020 international society of lymphology consensus document parallels advances in lymphology: An historical perspective.

Feasibility of markerless fluoroscopic real-time tumor detection for adaptive radiotherapy: development and end-to-end testing.

Respiratory-gated radiotherapy treatments of lung tumors reduce the irradiated normal tissue volume and potentially lower the risk of side effects. However, in clinical routine, the gating signal is usually derived from external markers or other surrogate signals and may not always correlate well with the actual tumor position. This study uses the kV-imaging system of a LINAC in combination with a multiple template matching algorithm for markerless real-time detection of the tumor position in a dynamic anthropomorphic porcine lung phantom. The tumor was realized by a small container filled with polymer dosimetry gel, the so-called gel tumor. A full end-to-end test for a gated treatment was performed and the geometric and dosimetric accuracy was validated. The accuracy of the tumor detection algorithm in SI- direction was found to be [Formula: see text] mm and the gel tumor was automatically detected in 98 out of 100 images. The measured 3D dose distribution showed a uniform coverage of the gel tumor and comparison with the treatment plan revealed a high 3D [Formula: see text]-passing rate of [Formula: see text] ([Formula: see text]). The simulated treatment confirmed the employed margin sizes for residual motion within the gating window and serves as an end-to-end test for a gated treatment based on a markerless fluoroscopic real-time tumor detection.

Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods.

BACKGROUND: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. METHODS: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. RESULTS: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001). CONCLUSIONS: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy. KEY POINTS: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Congenital chylothorax: Current evidence-based prenatal and post-natal diagnosis and management.

Congenital chylothorax is an uncommon condition but represents the main cause of congenital pleural effusion during the neonatal period. It usually appears before birth, both as an isolated disorder or in association with hydrops fetalis, negatively affecting the subsequent neonatal outcome. Prenatal treatment is usually considered to ensure a satisfactory lung development in case of moderate to severe pleural effusion or in the presence of hydrops, although consensus on treatment timing and modalities has not been reached to date. Both medical and surgical therapeutic strategies are available to treat this condition and novel treatment options have been recently attempted with acceptable results in both prenatal and post-natal setting. The heterogeneous clinical presentation of congenital chylothorax together with its rarity, its numerous etiologies and the absence of a highly effective treatment renders the diagnostic and therapeutic approach difficult to standardize. In addition, adequate visualization of the lymphatic system is complex, especially in small neonates, although new promising techniques have been developed lately and may contribute to improved management of this serious but infrequent condition. This review focuses on the current evidence base for the diagnosis and treatment options for congenital chylothorax, suggesting a rational diagnostic and therapeutic approach both in the prenatal and in the neonatal period.

Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes.

Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P <001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P <001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.