French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease.

Calciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine. PURPOSE: Calciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD). METHODS: We compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review. RESULTS: CPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients. CONCLUSION: Low hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

[POEMS syndrome: Diagnosis, stratification, treatments]. / Syndrome POEMS : diagnostic, prise en charge et traitements.

POEMS syndrome is a rare form of B-cell dyscrasia with multiple clinical signs including the acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. It is a paraneoplastic syndrome due to an underlying plasma cell disorder belonging to the monoclonal gammopathies of clinical significance (MGCS). The major criteria for this syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF), and the presence of Castleman's disease. Minor features include organomegaly, endocrinopathy, skin changes, papilledema, extravascular volume over-load, and thrombocytosis. The diagnosis of POEMS syndrome requires three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. VEGF plays a major role in the disease although anti-VEGF treatments have been disappointing. Risk stratification is based on clinical phenotype rather than specific molecular markers. Depending on bone marrow involvement and the number of sclerotic bone lesions, first line therapy should be irradiation or systemic therapy. For patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing irradiation therapy should receive antiplasma cell systemic therapy, the most effective being high dose chemotherapy with autologous stem cell transplantation. Lenalidomide seems to have a high efficacy with manageable toxicity. Thalidomide and proteasome inhibitors like bortezomib are also effective, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Multimodal imaging in radiotherapy: Focus on adaptive therapy and quality control.

Improved computer resources in radiation oncology department have greatly facilitated the integration of multimodal imaging into the workflow of radiation therapy. Nowadays, physicians have highly informative imaging modalities of the anatomical region to be treated. These images contribute to the targeting accuracy with the current treatment device, impacting both segmentation or patient's positioning. Additionally, in a constant effort to deliver personalized care, many teams seek to confirm the benefits of adaptive radiotherapy. The published works highlight the importance of registration algorithms, particularly those of elastic or deformable registration necessary to take into account the anatomical evolutions of the patients during the course of their therapy. These algorithms, often considered as "black boxes", tend to be better controlled and understood by physicists and physicians thanks to the generalization of evaluation and validation methods. Given the still significant development of medical imaging techniques, it is foreseeable that multimodal registration needs require more efficient algorithms well integrated within the flow of data.

Is anaesthesia of the deep branch of the lateral plantar nerve specific for the diagnosis of proximal metatarsal pain in the horse?

OBJECTIVES: To investigate the specificity of anaesthesia of the deep branch of the lateral plantar nerve (DB-LPN). METHODS: Twenty horses had DB-LPN anaesthesia performed by a single injection technique as part of a lameness investigation. The mechanical nociceptive threshold (NT) was measured using a handheld force meter at six points on the lateral aspect of the limb: before diagnostic anaesthesia (T0), and at 15 (T15) and 30 (T30) minutes post anaesthesia. Paired t-tests were performed and significance was set at p <0.05. In addition, ten cadaveric limbs were injected with 2.5 ml new methylene blue solution using a single injection technique to evaluate the extent of dye diffusion within the proximal metatarsal region. RESULTS: Compared with T0, there was a significant decrease in NT for all points combined at T15 (p = 0.008) and also at T30 (p = 0.007). There was a significant decrease in NT at T15 on the lateral third metatarsal bone (p = 0.012). At T30 there was a significant decrease in NT at the lateral sesamoid (p = 0.007), lateral third metatarsal bone (p = 0.031), and mid metatarsus (p = 0.033). Four out of 20 horses had a NT greater than 10 N at the lateral heel bulb at T30. In the cadaveric limbs, the total diffusion distance for all limbs (mean ± SD) was 70.4 ± 20.5 mm. Dye surrounded the DB-LPN in all limbs and the lateral plantar nerve (LPN) in nine out of 10 limbs. CLINICAL SIGNIFICANCE: Concurrent anaesthesia of the LPN is likely to occur when DB-LPN anaesthesia is performed using a single injection technique.

The first 100 thrombolysis cases in a novel Scottish mesh telestroke system.

Stroke thrombolysis has been a major driver for change within stroke services. However, until recently its widespread application has been limited to tertiary centres. Transfer to tertiary care can lead to significant delays in thrombolysis. We developed a novel mesh telestroke network, which allows stroke specialists to make videoconference-based thrombolysis decisions either from one of three stroke units or from home. We report data on the first 100 patients treated using this model and retrospectively review the first 100 strokes thrombolysed with tissue plasminogen activator across three stroke units. Prospectively collected data were extracted from the Stroke Audit In Lanarkshire database. Case notes were retrieved for clarification when necessary. Outcome measures were timings from symptom onset to infusion, post-thrombolysis symptomatic intracerebral haemorrhage and death. Fifty-one percent of cases were assessed by telestroke link. Median symptom onset to thrombolysis was 160 min (IQR 125-190). There were two symptomatic intracerebral haemorrhages, both in patients assessed face-to-face. Overall mortality was 14%. Our experience of tissue plasminogen activator is comparable to UK data extracted from SITS-MOST in overall timings and complication rates. This model of telemedicine could be replicated to provide safe thrombolysis to areas with challenging infrastructure, geography or insufficient stroke specialist cover.

Bioreactance is not reliable for estimating cardiac output and the effects of passive leg raising in critically ill patients.

BACKGROUND: Bioreactance estimates cardiac output in a non-invasive way. We evaluated the ability of a bioreactance device (NICOM®) to estimate cardiac index (CI) and to track relative changes induced by volume expansion. METHODS: In 48 critically ill patients, we measured CI estimated by the NICOM® device (CINicom) and by transpulmonary thermodilution (CItd, PiCCO2™ device) before and after a 500 ml saline infusion. Before volume expansion, we performed a passive leg raising (PLR) test and measured the changes it induced in CINicom and in pulse contour analysis-derived CI. RESULTS: Considering the values recorded before PLR and before and after volume expansion (n=144), the bias (lower and upper limits of agreement) between CItd and CINicom was 0.9 (-2.2 to 4.1) litre min(-1) m(-2). The percentage error was 82%. There was no significant correlation between the changes in CItd and CINicom induced by volume expansion (P=0.24). An increase in CI estimated by pulse contour analysis >9% during the PLR test predicted fluid responsiveness with a sensitivity of 84% (95% confidence interval 60-97%) and a specificity of 97% (95% confidence interval 82-100%). The area under the receiver operating characteristic curve constructed to test the ability of the PLR-induced changes in CINicom in predicting fluid responsiveness did not differ significantly from 0.5 (P=0.77). CONCLUSIONS: The NICOM® device cannot accurately estimate the cardiac output in critically ill patients. Moreover, it could not predict fluid responsiveness through the PLR test.

Deep digital flexor tendon injury within the hoof capsule; does lesion type or location predict prognosis?

The type and location of deep digital flexor tendon (DDFT) lesions may be important in predicting outcome. The objectives of this study were to determine the frequency of different types of DDFT lesions within the hoof capsule and to determine whether lesion type predicts return to athletic activity. Lesions of the DDFT were divided into: core lesions, dorsal border lesions and parasagittal splits. Lesion location was documented, and follow-up information was obtained by telephone survey at least 18 months after diagnosis. Of 168 horses with primary DDFT injury, 54 horses had dorsal border lesions, 59 had parasagittal splits and 55 had core lesions. Twenty-five per cent of all horses returned to previous levels of athletic activity within 18 months of MRI evaluation. Horses with complete splits or core lesions of the DDFT were significantly less likely to return to some level of athletic activity than horses with dorsal border lesions P<0.001. Dorsal border lesions of the DDFT appear to have a better prognosis than core lesions or parasagittal splits. This study provides additional information that may help clinicians predict the prognosis for different types of DDFT injury.

A comparative toxicogenomic investigation of oil sand water and processed water in rainbow trout hepatocytes.

The purpose of this study was to compare the expression of gene transcripts involved in toxic stress in rainbow trout hepatocytes exposed to oil sand water (OSW), lixiviate (OSLW), and processed water (OSPW). We pose the hypothesis that the changes in gene expression responses in cells exposed to a simulated oil sand extraction procedure (OSPW) differ from the gene expression responses of OSLW and OS. Rainbow trout hepatocytes were exposed to increasing concentrations of OSW, OSLW, and OSPW for 48 h at 15 °C. Cell viability was assessed by measuring membrane permeability, total RNA levels, and gene expression using an array of 16 genes involved in xenobiotic biotransformation (GST, CYP1A1, CYP3A4, MDR), metal homeostasis and oxidative stress (MT, SOD, and CAT), estrogenicity (VTG, ERß), DNA repair (LIG, APEX, UNG, and OGG), cell growth (GADD45 and PCNA), and glycolysis (GAPDH). The results showed that the toxicogenomic properties of OSPW differed from those of OSLW and OSW. Gene transcripts that were influenced by OSW and OSLW, and strongly expressed in OSPW, were MT, CAT, GST (induction), CYP1A1, VTG, UNG/OGG, and PCNA. These genes are therefore considered not entirely specific to OSPW but to water in contact with OS. We also found gene transcripts that responded only with OSPW: SOD, GST (inhibition), MDR (inhibition), CYP3A4, GAPDH, GADD45, and APEX. Of these gene transcripts, the ones strongly associated with toxicity (loss of cell viability and RNA levels) were CYP3A4, GST, and GAPDH. Genes involved in DNA repair were also strongly related to the loss of cell viability but responded to both OSLW and OSPW. The observed changes in cell toxicity and gene expression therefore support the hypothesis that OSPW has a distinct toxic fingerprint from OSLW and OSW.

Differential changes in gene expression in rainbow trout hepatocytes exposed to extracts of oil sands process-affected water and the Athabasca River.

The oil sands region of northern Alberta represents the world's largest reserves of bitumen, and the accelerated pace of industrial extraction activity has raised concern about the possible impacts on the Athabasca River and its tributaries. An ecotoxicogenomic study was undertaken on Oncorhynchus mykiss trout hepatocytes exposed to extracts of water samples near the oil sand development area, as well as to oil sands process-affected water (OSPW) extracts using the quantitative reverse transcriptase polymerase chain reaction technique. The expression of the following genes (mRNA) was monitored to track changes in xenobiotic biotransformation (CYP1A1, CYP3A4, glutathione S-transferase, multi-drug resistance transporter), estrogenicity (estrogen receptor and vitellogenin), oxidative stress (superoxide dismutase and metallothionein) and DNA repair activity (DNA ligase). The extent of DNA-aromatic hydrocarbon adducts was also determined in cells by immuno-staining. A comparative analysis of gene expression between the river/lake and OSPW samples revealed that CYP3A4, metallothioneins, DNA ligase and GST genes, were specifically expressed by OSPW. Cells exposed to OSPW, commercial naphthenic acids, and benzo(a)pyrene showed increased polyaromatic hydrocarbon DNA-adducts, as determined by cell immunofluorescence analysis. Other genes were induced by all types of water samples, although the induction potential was stronger in OSPW most of the time (e.g., VTG gene was expressed nearly 15-fold by surface waters from the lake and river samples but increased to a maximum of 31-fold in OSPW). A multivariate discriminant function analysis revealed that the lake and river water samples were well discriminated from the OSPW. The CYP3A4 gene was the most highly expressed gene in cells exposed to OSPW and responded less to the lake or river water in the Athabasca River area. This study identified a suite of gene targets that responded specifically to OSPW extracts, which could serve as toxicogenomic fingerprints of OSPW contamination.

Short-term temporal alterations in magnetic resonance signal occur in primary lesions identified in the deep digital flexor tendon of the equine digit.

REASONS FOR PERFORMING STUDY: Primary lesions of the deep digital flexor tendon (DDFT) within the digit are an important cause of lameness diagnosed using magnetic resonance imaging (MRI) but appearance of these lesions over time has not been documented. OBJECTIVES: To determine whether the magnetic resonance (MR) appearance of different primary DDFT lesions alter over a 6 month period and whether lesion type is a determinant of these changes. METHODS: Cases included had lameness attributable to a primary lesion involving the DDFT in the digit diagnosed on MRI. Lesions were typed into parasagittal, dorsal border and core lesions. Approximate volumes and intensities were quantified for each lesion type using T2* scan sequences. Follow-up examinations and measurements were repeated at 3 and 6 month periods following conservative management. RESULTS: Twenty-three horses fitted the inclusion criteria. Lesion distribution included: parasagittal (n = 7), dorsal border (n = 11) and core lesions (n = 5). No association was found between age of horse, degree of lameness and lesion type. Only dorsal border lesions showed statistically significant reduction both in volume (initial scan: 0.18 ± 0.14 cm(3) ) at 3 months (0.11 ± 0.10 cm(3) , P<0.05) and 6 months (0.05 ± 0.05 cm(3) , P<0.01) and ratiometric intensity (initial scan: 4.06 ± 1.54) at 6 months (2.00 ± 0.43; P<0.01). Parasagittal and core lesions showed no difference in lesion volume or ratiometric intensity. Lameness improved in all lesion types following conservative management. CONCLUSIONS: Dorsal border lesions of the DDFT show reduction in both volume and intensity whereas parasagittal and core lesions do not. POTENTIAL RELEVANCE: Lesion typing may be important in predicting lesion behaviour and short-term outcome using MR imaging.

An examination of the toxic properties of water extracts in the vicinity of an oil sand extraction site.

The industrial extraction of oil sands (OS) in northern Alberta, Canada, has raised concerns about the quality of the Athabasca River. The purpose of this study was to examine the toxic properties of various water extracts on Oncorhynchus mykiss trout hepatocytes. The water samples were fractionated on a reverse-phase C(18) cartridge and the levels of light-, medium- and heavy-weight polycyclic aromatic hydrocarbons (PAHs) were determined by fluorescence spectroscopy. Primary cultures of trout hepatocytes were exposed for 48 h at 15 °C to increasing concentrations of the C(18) extract corresponding to 0.02, 0.1, 0.5 and 2.5X concentrations from upstream/downstream sites in the Athabasca River, lake and groundwater samples, OS tailings and interceptor well-water samples. Changes in cell viability, phase I and phase II biotransformation enzymes (cytochrome P4501A and glutathione S-transferase activities), oxidative damage (lipid peroxidation LPO) and genotoxicity (single and double DNA strand breaks) were monitored in post-exposure cells. The water samples decreased cell viability and increased all the above endpoints at thresholds of between 0.02 and 0.1X the water concentration. The most responsive biomarker was DNA damage but it also offered the least discrimination among sites. LPO was higher at sites downstream of the industrial operations compared to upstream sites. A decision tree analysis was performed to formulate a set of rules by which to identify the distinctive properties of each type of water samples. The analysis revealed that OS tailings and interceptor waters were characterized by an increased concentration in light PAHs (>42 µg L(-1)) and this fraction represented more than 85% of the total PAHs. These samples also inhibited GST activity, which could compromise the elimination of genotoxic PAHs present in the system. An analysis of groundwater samples revealed a contamination pattern similar to that for OS tailings. There is a need for more research into specific biomarkers of toxicity from OS tailings compounds such as naphthenic acids, light PAHs among others, which are a characteristic fingerprint of OS extraction activities.

Impacts of pollution in feral Mya arenaria populations: the effects of clam bed distance from the shore.

This study examined the relationships between population characteristics and the expression of physiological biomarkers of stress in an intertidal clam population under pollution at sites differing in thermal history and coastline distance. The clam population metrics were age distribution, growth, condition factor, distance of the clam beds from the shore, and gonad development. Physiological biomarkers comprised biomarkers of defence such as superoxide dismutase, labile IIb metals in tissues, redox status of metallothioneins and glutathione S-transferase, of tissue damage such as lipid peroxidation and DNA strand breaks, of reproduction as determined by vitellogenin-like proteins and gonadosomatic index and immunocompetence such as phagocytosis and hemocyte viability. Age-related pigments were also examined to compare the physiological age of the clams with their chronological age. The results showed that all the above biomarkers were significantly affected at one of the two polluted sites at least. Distance from the shore was significantly correlated with most (81%) of the biomarkers examined. Clams collected at one polluted site were physiologically older than clams from the corresponding reference site. Canonical and adaptive regression (artificial neural networks) analyses found that the biomarkers measured in this study were able to predict the ecologically relevant endpoints. Biomarkers implicated in defense mechanisms, tissue damage and age-related pigments were most closely related to the clam population characteristics. Sensitivity analysis of the learning algorithm found that the following physiological and biochemical markers were the most predictive, in decreasing order, of clam population characteristics: glutathione S-transferase, phagocytosis, age pigments, lipid peroxidation in the gills, labile IIb metals and total MT levels. These biomarkers were affected by the distance of the clam beds from the shore, site quality (pollution) and reproduction activity.

A cDNA microarray assessment of gene expression in the liver of rainbow trout (Oncorhynchus mykiss) in response to a handling and confinement stressor.

A purpose-designed microarray platform (Stressgenes, Phase 1) was utilised to investigate the changes in gene expression within the liver of rainbow trout during exposure to a prolonged period of confinement. Tissue and blood samples were collected from trout at intervals up to 648 h after transfer to a standardised confinement stressor, together with matched samples from undisturbed control fish. Plasma ACTH, cortisol, glucose and lactate were analysed to confirm that the neuroendocrine response to confinement was consistent with previous findings and to provide a phenotypic context to assist interpretation of gene expression data. Liver samples for suppression subtractive hybridisation (SSH) library construction were selected from within the experimental groups comprising "early" stress (2-48 h) and "late" stress (96-504 h). In order to reduce redundancy within the four SSH libraries and yield a higher number of unique clones an additional subtraction was carried out. After printing of the arrays a series of 55 hybridisations were executed to cover 6 time points. At 2 h, 6 h, 24 h, 168 h and 504 h 5 individual confined fish and 5 individual control fish were used with control fish only at 0 h. A preliminary list of 314 clones considered differentially regulated over the complete time course was generated by a combination of data analysis approaches and the most significant gene expression changes were found to occur during the 24 h to 168 h time period with a general approach to control levels by 504 h. Few changes in expression were apparent over the first 6 h. The list of genes whose expression was significantly altered comprised predominantly genes belonging to the biological process category (response to stimulus) and one cellular component category (extracellular region) and were dominated by so-called acute phase proteins. Analysis of the gene expression profile in liver tissue during confinement revealed a number of significant clusters. The major patterns comprised genes that were up-regulated at 24 h and beyond, the primary examples being haptoglobin, beta-fibrinogen and EST10729. Two representative genes from each of the six k-means clusters were validated by qPCR. Correlations between microarray and qPCR expression patterns were significant for most of the genes tested. qPCR analysis revealed that haptoglobin expression was up-regulated approximately 8-fold at 24 h and over 13-fold by 168 h.